Cost-effectiveness of screening high-risk HIV-positive men who have sex with men (MSM) and HIV-positive women for anal cancer

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 05/11/02. The contractual start date was in December 2005. The draft report began editorial review in November 2009 and was accepted for publication in May 2010. As the funder, by devising a commissioning brief, the HTA programme specified the research question and study design. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

None

Copyright statement

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Introduction

Anal cancer is an uncommon cancer. It is a disease in which cancer (malignant) cells are found in the anus. Like most cancers, anal cancer is best treated when it is diagnosed soon after it develops. Primary treatment is generally concomitant radiotherapy (RT) and chemotherapy (if tolerated) to preserve the anal sphincter, but, despite these approaches, local disease failure is considerable, and requires salvage radical surgery with associated high morbidity and mortality. Anal cancer is predominantly a disease of the elderly and is near to zero in early life. The human papillomavirus (HPV), has been implicated as a causal agent of anal cancer. HPV infection, for the majority of cases, is transmitted sexually. The vulnerability of individuals with human immunodeficiency virus (HIV) to HPV infections has seen an increase in the number of cases from this population presenting with anal cancer.

To decide whether the screening of groups of people for a specific condition is suitable, there are well-defined criteria that can be used to aid the decision process. 1 The condition should be an important health problem, and the natural history and epidemiology must be understood. The test itself should be safe, simple, accurate and acceptable to the general population.

Aim of the review

The aim of this review is to estimate the cost-effectiveness of screening for anal cancer in men and women who are HIV positive, and, in particular, men who have sex with men (MSM), who have been identified as being at greater risk of the disease, by developing a model that incorporates all of the above criteria.

Epidemiology

Cancer is predominantly a disease of the elderly, with overall crude rates of cancer registrations of 462 per 100,000 of the population for males and 451 per 100,000 of the population for females in England for 2003,2 with anal cancer being no exception. Anal cancer is a rare disease; in 2003 there were 722 registrations of newly diagnosed malignant neoplasm of anus and anal canal in England, with 291 of registrations being male and 431 female. 2 Anal cancer is also very much a cancer of the elderly, with 37% (108) of males with newly diagnosed anal cancer being aged 65 or over and 56% (241) of females with newly diagnosed anal cancer being aged 65 or over. 2 For anal cancer, the rate per 100,000 of the general population in England 2003 was 1.2 per 100,000 for males and 1.7 per 100,000 for females (Table 1). 2

Incidence rate by age and gender

The probability of developing anal cancer rises sharply with age and the UK population is ageing. In young people, the risk is very low, but between the ages of 55 and 65 the annual incidence rate is approximately 3 per 100,000 for both males and females. Amongst those aged between 75 and 84 years, the annual incidence rate is over 5 per 100,000 and over 6 per 100,000 per year for males and females, respectively. Figure 1 shows the age-specific incidence rate for anal cancer, based on data from the Office of National Statistics. 2

FIGURE 1.

Annual incidence rate per 100,000 for newly diagnosed anal cancer by gender and age in England 2003. Compiled from data from the Office for National Statistics. 2

The annual incidence rate (directly age-standardised rates) has remained constant over the last decade, remaining at around 1.0 per 100,000 for males. For females, there has been a slight rise in directly age-standardised rates from the late 1990s, rising from around 1.0 per 100,000 to around 1.2 per 100,000 (Figure 2).

FIGURE 2.

Directly age-standardised rate per 100,000 for newly diagnosed anal cancer by gender in England 1994–2003. Compiled from data from the Office for National Statistics. 2

In 2006, Brewster and Bhatti9 publicised the findings of their study describing secular trends in incidence of SCC of the anus in Scotland, before and during the HIV epidemic. Incidence cases of malignant neoplasms of the anus and anal canal were extracted from the Scottish Cancer Registry for the years 1975–2002. Brewster and Bhatti9 identified 757 cases of SCC (278 males and 479 females) registered, with an incident date falling within the 28-year period of the study. The authors found that in males the standardised incidence rate per 100,000 increased from 0.14 to 0.17 in the late 1970s to around 0.37 in the late 1990s, with a peak of 0.44 in the period 1993–7. For females, the incidence rate was generally higher, increasing from 0.23–0.27 in the late 1970s to a peak of 0.55 in the period 1998–2002.

HPV infection

The natural history of HPV infection is complex, and clearance and persistence of viral DNA, along with progression to squamous intraepithelial lesions (SILs), vary depending on the viral type and patient characteristics, such as age and immune status. 18

Palefsky et al. 19 reported in 1998 the findings of a cohort study to characterise the prevalence of 29 different HPV types and the mixture of 10 additional types in the anal canal among HIV-positive and HIV-negative men. Palefsky et al. 19 recruited 346 HIV-positive and 262 HIV-negative men from among homosexual and bisexual men in the San Francisco Men’s Health Study (SFMHS) in the San Francisco General Hospital Cohort Study (SFGH) and the University of California, San Francisco (UCSF), responding to newspaper advertisements. The participants were interviewed regarding their medical history, prescribed drug use, X-ray exposure, hospitalisation, transfusions, history of sexually transmitted diseases, intestinal parasites, hepatitis anal conditions (such as fissures and fistulas) and symptoms related to HIV. The participants were also asked about sexual practices, cigarette smoking, drinking and recreational drug use. Participants also tested underwent HPV testing. Palefsky et al. 19 reported no differences between HIV-positive and HIV-negative men.

Kreuter et al. 20 conducted a prospective cohort study in Germany to determine the clinical spectrum of AIN and lesional HPV colonisation in a cohort of homosexual men who were HIV-positive and had a history of receptive anal intercourse. Between December 2003 and July 2004, 103 homosexual men with a laboratory-confirmed diagnosis of HIV were recruited for a screening programme for AIN. The participants underwent a standardised interview on medical history, STDs, history of HPV-related diseases and tobacco use before screening.

Kreuter et al. 20 reported that of all patients 86% had anal HPV infection at their first visit. AIN was diagnosed in 20 (19.4%) of the 103 participants. The authors concluded that their data confirmed the high incidence and prevalence of inpatients with AIN who are HPV positive with HIV infection. The authors of this paper were of the opinion that standardised screening programmes for anal cancer prevention and treatment protocols for AIN in patients infected with HIV must be implemented.

Watson et al. 21 in 2006 reported on a prospective cohort of 72 patients (52 women, 20 men) who were diagnosed with AIN between January 1996 and December 2004. These 72 patients, from a single institution in New Zealand, were identified from a prospective database. Data collected from the database were supplemented with information from patient chart review, which included data on age, sex, HIV/AIDS infection, chronic immunosuppression, disease presentation, management and follow-up. All patients underwent biopsy or perianal skin excision between January 1996 and July 2005; 17 patients were initially diagnosed with AIN 1, 10 with AIN 2, and 45 with AIN 3 on first biopsy. A total of 42 patients also had pathological changes that were consistent with HPV infection. Seven patients were recipients of renal transplants and were on immunosuppressive therapy. Five patients were HIV positive and 10 others were on long-term immunosuppressive therapy for other causes.

Watson et al. 21 detailed that, during the study period, 193 procedures were carried out (127 were biopsies only and 66 were perianal skin excisions). Eight patients progressed to develop SCC during the study period (median time 42 months). There was histological evidence of progression in 11 patients, with six patients having AIN 3 progressing to have anal SCC. Two patients with AIN 2 developed cancer and 25 patients with AIN had regression of dysplasia. The conclusion reached by Watson et al. 21 was that their study suggested that patients with HG-AIN are at a higher risk of developing anal SCC than previously thought and surveillance is indicated. The authors also concluded that the patients who are particularly at risk are the immunocompromised, and that the treatment available at present does not prevent AIN in some patients from progressing to invasive cancer and carries the associated risk of faecal incontinence. Watson et al. 21 further concluded that as a result of their study they could not recommend screening of asymptomatic high-risk populations, but that there is a need for research into more effective and less morbid treatments for this disease.

Prognosis

The staging system for anal cancer is the TNM (tumour, node, metastasis) staging system. 22 The TNM staging system is useful for surgical purposes, such as providing guidelines on the extent of resection, it is described in more detail below.

The TNM staging system is based on the anatomical extent of spread, where, T refers to the extent of the primary tumour, N refers to the extent of nodal metastases and M refers to the presence or absence of distant metastases. Each of these three factors is given a number: for T, the number indicates how large the tumour is; for N, the number informs which lymph nodes have cancer cells in them; and for M, the number informs as to whether the cancer has spread to other parts of the body – in general, the higher the number, the more serious the cancer. There are five stages of tumour size in the current TNM classification of anal cancer: T1–T4 and a very early stage called Tis or carcinoma in situ. Anal cancers are not usually found at this very early stage, as they do not cause any symptoms when they are so small. Below are descriptions of each T stage for anal cancer:

• Tis or carcinoma in situ The earliest stage of anal cancer, when the cancer cells are found only inside the lining of the anus and have not spread elsewhere.

• T1 The tumour measures 2 cm across or less.

• T2 The tumour is larger than 2 cm but smaller than 5 cm.

• T3 The tumour is larger than 5 cm.

• T4 The cancer can be any size, but is growing into the surrounding tissues or organs, such as the urethra, the vagina or bladder.

Staging is a process that tells the clinician how widespread the cancer may be at the time of diagnosis. It will show whether the cancer has spread and how far. The treatment and outlook for anal cancer depends, to a large extent, on its stage.

In 2004, Johnson et al. 3 reported 5-year survival figures of 58% for males and 64% for females, based on data collected between 1973 and 2000 on diagnosis and outcomes of invasive and in situ anal cancer. The data came from the SEER programme in the USA. Lower 5-year survival figures were reported by Bower et al. 23 for a cohort of English patients with HIV (25 MSM and 1 heterosexual woman) with confirmed cases of invasive anal cancer. Bower et al. 23 reported a 5-year overall survival figure of 47%.

In 2006, Karandikar et al. 4 reported a 5-year overall survival figure of 45%, based on a cohort of patients with anal cancer who were identified from a 5-year audit (1995–9) of anal cancer in Wales.

Also in 2006, Jeffreys et al. 24 reported the results of a study that was based on all first, primary, invasive malignant cancers of the rectum and anus – excluding anal margin and skin – that were diagnosed in adults (15–99 years) and registered in the National Cancer Registry for England and Wales between 1986 and 1999. The aims of the study were to investigate the effects of tumour and patient characteristics on trends in the survival of patients with cancer of the anus or rectum in England and Wales. A total of 132,542 adults who were diagnosed during the 14 years were followed up to 2001 through the National Health Service Central Register. Results were given for patients diagnosed during the calendar periods 1986–90, 1991–5 and 1996–9. Relative survival up to 5 years after diagnosis was estimated, using deprivation-specific life tables. Five-year relative survival rose by about 10% overall, from 38% (1986–90) to 48% (1996–9) in men, and 39% (1986–90) to 51% (1986–90) in women.

Gatta et al. 7 gave details on survival and incidence from rare cancers using data collected from 18 European countries. They reported that the overall 5-year relative survival for anal SCC was good at 53.1% (95% CI 51.5 to 54.8); the authors also reported absolute survival figures, with 53.1% (95% CI 51.7% to 54.4%) for 3-year survival and 43.3% (95% CI 41.9% to 44.6%) for 5-year survival.

For the UK, Gatta et al. 7 reported a 5-year relative survival of 51.9% (95% CI 49.7% to 54.2%). Data for the UK (England, Scotland and Wales) came from national cancer registries or from regional cancer registries.

Quality of life

Allal et al. 25 undertook a study to assess long-term quality of life (QoL) in patients treated by RT with or without chemotherapy. The study population was drawn from 165 patients with anal carcinoma who received sphincter-conserving treatment using RT, with or without chemotherapy, between January 1976 and December 1994. Patients were considered for the study’s QoL assessment if they were 80 years old or less and were alive without disease activity at least 3 years after completion of treatment with a functioning anal sphincter. In total, 52 patients satisfied the inclusion criteria – 49 patients were contacted by telephone to request their participation in the study and three were contacted by mail. Of these patients, 46 patients agreed to participate, one refused, two were assessed to be ineligible because of serious comorbidities and the three contacted by mail did not respond. Among the 46 patients who received the two questionnaires, five refused to complete them for different reasons (two ‘unclear’, two ‘number of questions’, one ‘questions relating to sexual aspects’). This left 41 patients for the analysis.

The QoL questionnaires used by Allal et al. 25 were developed by the QoL Study Group of the European Organisation for Research and Treatment of Cancer (EORTC). One was a validated questionnaire assessing cancer-specific QoL (EORTC QLQ-C30) (Aaronson et al. 1993) and one assessing site-specific (colorectal) QoL (EORTC QLQ-CR38), which at the time of the study was in the process of validation.

The EORTC QLQ-C30 is a patient self-rating questionnaire that comprises six multi-item function scales measuring physical, role, social, emotional and cognitive functions, along with overall QoL. Separate symptom scales are included to assess pain, fatigue and emesis, and five single items to measure gastrointestinal symptoms, dyspnoea, appetite loss and sleep disturbances. A final item evaluates the perceived economic consequences of the disease.

The EORTC QLQ-CR38 is a patient self-rating questionnaire that comprises 38 questions, of which 19 are completed by all patients and the remaining by a subset of patients (males or females, patients with or without a stoma). The general structure comprises four multi-item/single-function scales, seven multi-item symptom scales and one single symptom item. The functioning scales assess effects on micturition, chemotherapy, side effects, gastrointestinal general symptoms, defecation problems, stoma-related problems and sexual dysfunction in males or females. The single symptom item assesses weight loss.

The result reported by Allal et al. 25 for the EORTC QLQ-C30 questionnaire was that the physical function scale scores did not differ significantly in the subgroups, although older patients tended to report lower scores (p = 0.08). For the role function scale, while non-significant, the severity of late complications and poor MSK (Memorial Sloan-Kettering Center anal function criteria) anal function appear to have a negative effect (p = 0.08 for both). For the emotional and the social function scales, no significant differences were noted between the different subgroups. However, the overall QoL score was significantly affected by the severity of late complications (p = 0.005) and the anal function score (p = 0.04). This score did not differ with the current age and pain symptom scales, particularly according to the length of follow-up.

The results of the EORTC QLQ-CR38 questionnaire used by Allal et al. 25 were that body image function score was significantly lower only in patients with advanced T stage (p = 0.003). For the future perspective function scale, no significant differences were noted between subgroups, while lower scores were reported in patients with higher grade of late complications (p = 0.1). The sexual functioning score was significantly lower only in the advanced-age subgroup (p = 0.01). None of the function scale scores seemed to be influenced by the length of follow-up. A significantly higher defecation problems score was reported in patients who were treated with brachytherapy for the boost (p = 0.03).

Allal et al. 25 concluded that in patients treated with sphincter conservation for anal carcinomas, long-term QoL, as measured by the EORTC QLQ-C30 and QLQ-CR38, appeared to be acceptable, with the exception of diarrhoea and, perhaps, sexual function. The subset of patients who presented with severe complications and/or anal dysfunction showed poorer scores in most scales.

In 2005, Pachler and Wille-Jorgensen26 reported on a systematic review of QoL after rectal resection for cancer, with or without permanent colostomy. The objective of the review was to evaluate the QoL in patients treated for rectal cancer with either abdominoperineal excision (APE), with a permanent stoma or rectal anastomosis anterior resection (AR) with preservation of the sphincter function.

The criteria for considering studies to use in the review by Pachler and Wille-Jorgensen26 were:

• All controlled clinical trials and observational controlled studies in which QoL in patients with rectal cancer, having either APE or AR were studied using a multidimensional QoL instrument.

• The participants were individuals with verified cancer of the rectum, which had been treated with either APE or AR.

• No discriminatory criteria concerning age, gender, race or social status.

• Quality-of-life assessments using validated multidimensional questionnaire, self-reported questionnaires completed by the patient – a relative or independent rater was considered eligible for inclusion.

• Assessments of functional results or one-dimensional aspects of QoL (e.g. sexual function, urinary function, pain) were not included in the review.

Pachler and Wille-Jorgensen26 reported that 30 potential studies were identified, 11 of these, including 1412 participants (range 23–372), met the inclusion criteria. None was randomised, nine were retrospective and two prospective. Overall, six studies found that patients undergoing APE did not have poorer QoL than patients undergoing AR. One study found that a stoma only slightly affected the patient’s QoL; four found that after APE patients had significantly poorer QoL than after AR. The authors concluded that it was not possible to draw conclusions whether the QoL measures of stoma patients are poorer than for non-stoma patients. However, the results challenge the assumption that people with stoma fare less well than non-stoma patients.

Search strategies

A comprehensive literature search was undertaken in January 2006 (updated in November 2006) to identify relevant literature pertaining to screening high-risk groups for anal cancer. Four major searches were conducted, which were designed to retrieve papers:

• describing the epidemiology of anal cancer

• on the effectiveness of screening technologies for anal cancer

• on the effectiveness of different screening programmes/policies for anal cancer

• on the cost-effectiveness and comparative costs of candidate technologies/programmes/policies identified from effectiveness searches. Searches were also undertaken to retrieve papers on the effectiveness of different treatments for anal cancer.

The following electronic bibliographic databases were searched:

1. Applied Social Sciences Index and Abstracts (ASSIA)

2. BIOSIS previews (Biological Abstracts)

3. British Nursing Index (BNI)

4. Cumulative Index to Nursing and Allied Health Literature (CINAHL)

5. Cochrane Database of Systematic Reviews (CDSR)

6. Cochrane Central Register of Controlled Trials (CENTRAL)

7. EMBASE

8. MEDLINE

9. MEDLINE In-Process & Other Non-Indexed Citations

10. NHS Database of Abstracts of Reviews of Effects (DARE)

11. NHS Health Technology Assessment (HTA) Database

12. PsycINFO

13. Science Citation Index (SCI)

14. Social Sciences Citation Index (SSCI).

Attempts were also made to identify ‘grey’ literature by searching appropriate databases (e.g. the King’s Fund, DH-Data) current research registers [e.g. National Research Register (NRR), Current Controlled Trials (CCT) register]. A general internet search was also conducted using a standard search engine (Google) and a meta-search engine (Copernic).

The reference lists of included studies and relevant review articles were also checked.

No date or language restrictions were applied to these searches. The search strategies used in MEDLINE (Ovid) are displayed in Appendix 3.

All prospective and retrospective primary studies groups who were at high risk of anal cancer were included in the review. An assessment was conducted of published literature identified by the search strategy by all four reviewers. All publications were divided into the following broad categories based initially on their titles and abstracts (where available): cost-effectiveness, natural history, prevalence, diagnosis, epidemiology, screening, treatment, risk, QoL, and not relevant – excluded. A paper could be included in more than one category. The reviewers then obtained copies of all papers not excluded. Some papers were reclassified after reading the full text, additional papers were subsequently excluded. Each paper not excluded after the initial readings was given a unique identifier. Hand searching of included papers was conducted to identify any relevant papers not detected by the electronic searches. A quality of reporting of meta-analyses (QUOROM) trial flow chart is displayed in Appendix 4.

Inclusion/exclusion criteria

Papers were selected if they met the following inclusion criteria:

• contained data on population incidence, effectiveness of screening, health outcomes or screening and/or treatment costs of anal cancer

• described defined suitable screening technologies

• prospectively evaluated a test, or a combination of tests, to detect anal cancer.

Papers were excluded if they were a foreign language publication.

Data abstraction

Data from all of the studies meeting the inclusion criteria were extracted into data extraction forms by the clinical effectiveness reviewer.

Screening

This section reviews studies that evaluated screening procedures for the detection of AIN, anal squamous intraepithelial lesion (ASIL) or anal cancer. Ten studies were identified for inclusion on screening; Table 3 shows the studies characteristics and Appendix 5 gives details on study quality. Nine studies were cohort studies27–35 and one was a systematic review. 36

The reporting quality of the screening studies is generally poor, making it difficult to assess the true quality of the work undertaken. Only one of the studies is randomised. The remaining studies are cohort studies. The data tend not to be analysed on an intention-to-treat basis and assessors are not blinded.

Treatment

Six studies40–45 were identified and included in this review: Table 5 displays characteristics of the studies and Appendix 6 gives details on study quality. The criteria of the National Screening Committee (NSC) for appraising the viability, effectiveness and appropriateness of a screening programme (Appendix 2) states that there should be an effective treatment or intervention for patients identified through early detection, with evidence of early treatment leading to better outcomes than late treatment. Therefore, survival from treatment options is of interest. For completeness, comments from an editorial38 and Effective Health Care bulletin issued in March 200439 are included at the end of this section.

In Chapters 1 and 3 risk is used in a descriptive and general sense; in this chapter, risk is used in the context of modelling and does not necessarily draw upon the same evidence.

Anal cancer is a rare neoplasm that affects the epithelium of the anal canal. The increased incidence in men, particularly in the USA is etiologically related to a sexually transmitted agent. 48 HPV has been implicated as a causal agent of anal cancer.

Risk of anal cancer is near to zero in early life. Sexual activity is virtually essential for transmission of HPV. Multiple partners bring the risk of a greater variety of strains, and, in turn, a greater chance of a more dangerous strain (with regard to anal cancer). Other genitourinary (GU) infections may be a marker of multiple sexual partners, sex with infected individuals and high-risk behaviour. There may be some potential of HPV infection with some other GU infections. The criteria for appraising screening programmes1 list the importance of there being a detectable risk factor when considering implementing a screening programme.

Once HPV infection occurs, the dysplastic process at the anal margin follows more frequently with certain types of HPV, and appears to be seen more frequently where receptive anal intercourse occurs.

Infection with HIV has a profound effect on the immune system. It is the immune system that fights infection but also this same system guards against dysplastic changes. It is this latter role that explains much of the increased cancer risk in patients with HIV and AIDS.

Kim et al. 49 undertook a retrospective cohort study, comparing HIV-positive and HIV-negative patients with respect to treatment tolerance and outcome. HIV-positive and HIV-negative patients were compared by age, gender, sexual orientation, stage at diagnosis, treatment provided, response to treatment, tolerance and survival.

Kim et al. 49 reviewed the records of 98 patients with anal neoplasms. Seventy-three patients had invasive anal epidermoid (squamous or cloacogenic) carcinoma and formed the study group.

Of the 73 patients, 13 were HIV-positive and 60 were HIV-negative. Biopsies were performed on all primary tumours. Preoperative staging was performed using examination, anal ultrasound, chest X-rays and computerised tomography (CT) scanning. After completion of primary therapy, patients were seen every 2–3 months for 3 years, every 6 months until the end of the fifth year, and then annually. Post-treatment evaluation included a careful clinical examination with digital palpation and anoscopy at each visit.

The findings by Kim et al. 49 were that the HIV-positive and HIV-negative groups differed significantly by age (42 vs 62 years, p < 0.001), male gender (92% vs 42%, p < 0.001) and homosexuality (46% vs 15%, p < 0.05). The authors found that there were no differences by stage at diagnosis or radiation dose received. Acute treatment major toxicity differed significantly (HIV-positive 80% vs HIV-negative 30%, p < 0.005). Kim et al. 49 reported that only 62% of HIV-positive patients were rendered disease free after initial therapy versus 85% of HIV-negative patients (p = 0.11), and that the median time to cancer-related death was 1.4 vs 5.3 years (p < 0.05). A survival model did not show age, gender, stage or treatment to be independent predictors.

Kim et al. 49 found that HIV-positive patients with anal carcinoma seemed to be a different population from HIV-negative patients by age, gender and sexual orientation. They have a poorer tolerance for combined therapy and a shorter time to cancer-related death. A strong trend to poorer initial response rate was also seen.

Once dysplasia has occurred, progression to higher levels of dysplasia [from low-grade squamous intraepithelial lesions (LSILs) to HSILs] takes place over time. This progression is seen at an increased rate in persons with HIV (regardless of how contracted).

Once anal cancer is present, prognosis is better in patients with an intact immune system. Patients with HIV and AIDS have a poorer prognosis despite having developed the cancer at a younger age.

The first diagram in Appendix 7 summarises the life course model for this condition. The second diagram shows how this model is modified for HIV-negative women.

High-risk groups

Men who have sex with men may identify themselves as homosexual or bisexual, and these men are at increased risk for STDs such as HIV infection, HPV and anal cancer. Knight50 reported that many men are engaging in dangerous sexual practices that may jeopardise their health. These sexual practices include anal sex without a condom (‘bare backing’), oral sex without a condom, oral stimulation of the anus (‘rimming’) without protection, multiple sex partners at one time and use of illicit drugs.

Halperin51 reported in 1999 the results of a review examining the practice of anal sex among heterosexual population, related sociocultural factors and risk of associated health problems. Halperin51 stated that heterosexual anal sex remained understudied, but that analysis of available evidence suggesting that this stigmatised behaviour is not so rarely practised among heterosexuals. The review reported that surveys from North America, Europe and Australia suggest that between 7% and 25% of the population reported practising heterosexual anal intercourse. For men, surveys from the late 1980s and early/mid 1990s suggest that approximately 2–5% of men reported having a same-sex experience, although only a small proportion of these engage in receptive anal intercourse.

Dodds et al. 52 reported the findings of an annual behavioural survey of homosexual men (from 1996 to 2000) who socialised in gay venues across London. Participants completed a short anonymous self-completion questionnaire covering demographic details, sexual health service use, HIV testing history, self-perceived HIV status and sexual behaviour. The authors found that the proportion of men having unprotected anal intercourse (UAI) increased significantly each year from 30% in 1996 to 42% in 2000 (p < 0.001).

In 1997, Frisch et al. 53 reported on a population-based case–control study, undertaken in Denmark and Sweden to examine if the incidence of anal cancer had increased, particularly amongst women. The authors conducted telephone interviews with 324 women and 93 men in whom invasive or in situ anal cancer was diagnosed between 1991 and 1994, 534 controls with adenocarcinoma of the rectum and 554 population controls. The interviews covered a wide spectrum of possible risk factors for anal cancer. ORs were calculated by logistic regression. Specimens of anal cancer tissue and samples of rectal adenocarcinomas were tested for HPV DNA using PCR.

Frisch et al. 53 searched national cancer registries in Denmark and Sweden to identify all incident cases of histologically verified invasive or in situ anal or rectal epidermoid carcinoma (anal cancer) reported during the period from 1991 to 1994. Danish patients were considered eligible for the study if the tumour was rectum, anal canal, anus, anorectum or perianal skin. Swedish patients were eligible if the topography was anus or rectum. The authors also included two control groups, with one group consisting of patients with adenocarcinoma of the rectum, who were chosen as controls to minimise any possible bias due to differential recall between patients with anal cancer and controls. The other control group consisted of persons from the general population. For the men, we tried to match two patients with rectal adenocarcinoma and two population controls to each patient with anal cancer, and for the women, a 1 : 1 : 1 match was sought. Controls were frequency matched within each country for sex and age (in 5-year intervals, except for the youngest patients in the cancer control group, because of the rarity of rectal cancer in young persons), and the patients with rectal adenocarcinoma were matched for the year of the diagnosis.

Overall, 417 patients with anal cancer (93 men and 324 women), 534 controls with adenocarcinoma of the rectum (191 men and 343 women), and 554 population controls (205 men and 349 women) were interviewed. The participation rate was 78–79% among female patients (cases and cancer controls) and 71–73% among male patients. Participation rates were 60–61% among population controls of both sexes.

Frisch et al. 53 found that, for men, indicators of sexual promiscuity were positively correlated with the risk of anal cancer. Among men who reported ever having had heterosexual intercourse, there was a statistically significant trend towards an association between the lifetime number of female sexual partners and the risk of anal cancer, with men reporting a total of two or three partners at lowest risk (p-value for trend = 0.004). Men with 10 or more female partners had 2.8 times the risk of those with two or three partners. Twenty-three per cent of patients with anal cancer, compared with 15% of controls, reported having visited a prostitute [OR 1.8 (95% CI 0.99 to 3.2)]. Unmarried men were at high risk for anal cancer: among those who did not report a current heterosexual relationship, the OR was 3.3 (95% CI 1.5 to 7.3), and among those who lived with a female partner, the OR was 8.7 (95% CI 3.1 to 25.0).

Men with HIV

MSM (without HIV)

In 1982, Daling et al. 71 reported on a study looking at whether characteristics that are correlated with male homosexual behaviour are associated with the incidence of cancer. The authors linked patients’ names on a population-based cancer reporting system covering 13 Washington counties in the USA, with names on the Washington State Department of Social and Health Services syphilis registry, as syphilis was believed to be correlated with homosexual activity. Of 47 men identified to have anal cancer, eight were considered to have syphilis, when the authors expected 0.4, based on the proportion of syphilis cases among men with other sites of cancer, thus suggesting that anal intercourse may be a risk factor for anal cancer.

Daling et al. 71 did state that the incidence of anal cancer was not high, either in men in general (approximately 1.1 per 100,000) or in homosexual men (the rate of which was unknown). The report authors, assuming that homosexual men have an anal cancer risk of 25–50 times that of heterosexual men, believed the annual incidence of anal cancer in homosexual men would be only between 12.5 and 36.9 per 100,000.

Chin-Hong et al. 72 reported findings from the EXPLORE study on age-related prevalence of HPV infection in HIV-negative MSM in 2004 and 2005. The authors reported on age-related prevalence of anal cancer precursors in HIV-negative MSM. The EXPLORE study, a randomised clinical trial of the efficacy of a behavioural intervention to reduce the risk of HIV acquisition in sexually active HIV-negative MSM, recruited participants from four cities in America (Boston, Denver, New York and San Francisco). Males were eligible for inclusion into the study if aged 16 years or older and reported as having receptive or insertive anal intercourse with one or more men within the preceding year. The study recruited 1409 men, with a median age of 37 years (interquartile range 31–43) and the median age at first receptive anal intercourse was 20 years (interquartile range 17–24). During the 6 months preceding entry into the study, the participants reported a median of eight sexual partners (range 4–20) and 77% reported having receptive anal intercourse.

In 2004, Chin-Hong et al. 72 reported on 1218 participants of the EXPLORE study: 8% reported a history of injection drug use and 49% were current smokers or had smoked in the past. Using PCR testing, the authors found that 57% of the HIV-negative MSM were HPV positive, and that 26% were infected with a high-risk HPV type, indicating that a high proportion of HIV-negative MSM may be at risk for developing anal cancer.

In 2005, Chin-Hong et al. 73 reported on a cross-sectional analysis of prevalence and determinants of ASIL in 1262 of 1409 HIV-negative MSM recruited to the EXPLORE study, for whom anal cytology and behavioural data were obtained. From an earlier analysis of participants of the EXPLORE study, it was believed that HIV-negative MSM are a population that is at an increased risk for the development of invasive anal cancer compared to the general population. It was reported that factors statistically significantly associated with ASIL were having more than five receptive anal sex partners compared with fewer than two receptive anal sex partners during the previous 6 months [OR 1.8 (95% CI 1.1 to 2.8), p = 0.018], older age at first receptive anal intercourse [OR 1.3 per 10-year increase in age (95% CI, 1.0 to 1.7), p = 0.045], injected drug use two or more times per month compared with no use in the previous 6 months [OR 17 (95% CI 1.2 to 223), p = 0.035], PCR evidence of an anal HPV infection [OR 2.5 (95% CI 1.3 to 4.9), p = 0.008] and anal HPV infection with increasing numbers of HPV type (p < 0.001 for linear trend). Although neither age nor smoking status were statistically significantly associated with ASILs in univariate analysis, the authors included both factors in the final multivariate model because previous studies had indicated that they are important risk factors for anal cancer.

In summary, the findings of these three studies indicate that HIV-negative MSM are at an increased risk of anal cancer due to receptive anal intercourse.

Females with HIV

In 1999, Hankins et al. 74 reported on a study undertaken to explore risk factors for HPV infection in HIV-positive women using data from the Canadian Women’s HIV Study, a prospective open cohort study that recruited HIV-positive women at 28 sites across Canada. HPV test results were available for 375 women, with a median age of 32.5 (range 16.5–77.3) years. It was reported that sexual transmission was the most frequent source of HIV infection (69.9%, n = 262); 14.1% (n = 53) were infected through injection drug use and 9.1% (n = 34) through the receipt of infected blood or blood products. Overall, two-thirds (67.2%, 252 out of 375) of the women were positive for HPV, with 28.8% having more than one HPV type. The global prevalence of high-risk oncogenic HPV types (16, 18, 45 and 56) and of intermediate-risk oncogenic HPV types (31, 33, 35, 39, 51, 52 and 58) in the cohort was 32.3%.

The findings from this study74 indicated, when HPV prevalence was examined by age, a consistent inverse relation between the presence of HPV and age (p = 0.006). HPV infection was found in 74.6% (141 out of 189) of women under the median age of 32.5 years, as compared with 59.7% (111 out of 186) of older women (p = 0.002).

In 2001, Holly et al. 75 reported on a study that evaluated HPV-related abnormalities in 251 HIV-positive women and 68 HIV-negative women from the San Francisco Bay Area site of the multicentre Women’s Interagency HIV study between the years 1995 and 1997. Questionnaire data on medical history and relevant sexual practices was obtained and study participants underwent a physical examination. The study was conducted before HAART therapy became widely available.

Holly et al. 75 found that their study indicated that HIV-positive women were at higher risk of abnormal anal cytology than high-risk HIV-negative women. Risk factors for abnormal cytology in HIV-positive women included detection of anal HPV DNA, a lower number of CD4 cells, a higher plasma level of HIV ribonucleic acid (RNA), a history of receptive anal intercourse and concurrent abnormal cervical cytology.

The two studies in this section suggest that that women who are HIV-positive, particularly younger HIV-positive women, are of high risk of HPV infection.

Females with higher risk of anal cancer

Anal cancer screening model structure

The anal cancer model structure develops the published models used by Goldie et al. 81,82 to evaluate anal cancer screening in HIV-negative and HIV-positive MSM. The model describes progression of anal cancer from no AIN lesions, to either low or HG-AIN lesions, and from HG-AIN lesions to anal cancer. Individuals’ low-grade anal intraepithelial neoplasia (LG-AIN) lesions may either regress to a healthy state or progress to the high-grade lesion state.

Figure 3 presents the structure of the model used in the current analysis. The major difference to the Goldie model81,82 is that the current model structure combines HIV-negative, undiagnosed HIV-positive, and diagnosed HIV-positive MSM in the same model. Goldie et al. 81,82 modelled HIV-negative and HIV-positive MSM separately so that their model did not allow for the transition from HIV negative to HIV positive, and it was not clear how undiagnosed HIV-positive MSM were modelled (the implicit assumption was that all HIV-positive MSM were diagnosed).

FIGURE 3.

Anal cancer model structure.

Thus, the baseline (natural history) model allows for the parallel description of the incidence and progression of HIV infection (through three decreasing CD4 count categories), the incidence and progression of anal cancer and its precursors (including the regression of LG-AIN), the diagnosis of HIV infection and the diagnosis of anal cancer and its precursors.

Another difference is that Goldie et al. 81,82 described the existence of ASCUS as a separate state that was handled by assuming that 24% of men in this state had underlying LSILs and 18% had underlying HSILs. It was not clear how this aspect was handled practically, for example did these proportions move to these states and the others to a normal state? In the current model, it is assumed that an ASCUS screening results is a positive test results, and screening test characteristics (i.e. sensitivity and specificity) are estimated accordingly. The resource implications of the differential processing of ASCUS and more definitive positive test results are assumed to be minor.

Alternative screening programmes are overlaid on the natural history, which act to increase the likelihood of detection of anal cancer in individuals eligible for screening in the years in which screening is offered.

The main screening model was developed as a cohort Markov model, so exact estimates of costs and benefits were estimated for each set of input parameters analysed. It was implemented in Microsoft excel spreadsheets, with associated macros. Submodels (as described below) were also developed as cohort Markov models in Microsoft excel.

The model moved forward in cycles of 1 year. It is recognised that disease may progress through multiple stages within a single year, but, as an annual screening programme was the shortest interval tested, the improvements in accuracy from reducing the cycle length were not considered to justify the necessary increase in model complexity. The time horizon of the model followed MSM to a maximum age of 100 years. The starting age of the model was varied to reflect the current distribution of MSM (this aspect is explained in more detail in the following section).

Model population

The subsequent sections describe the data, analyses and assumptions used to populate the model. The separate sections describe the estimation of the age-specific size of the MSM population; the incidence and progression of HIV infection; the incidence and progression of AIN lesions; the effects of treatment of precancerous and cancerous AIN lesions; the model’s screening-related parameters (screening attendance, as well as test sensitivity and specificity); and costs and utility weights associated with different events and states included in the model.

Anal cancer epidemiology and natural history

Values for the following anal cancer transition probabilities were required:

• no AIN to LG-AIN

• no AIN to HG-AIN

• progression from LG-AIN to HG-AIN

• progression from HG-AIN to early stage invasive cancer

• progression from early stage invasive cancer to late stage invasive cancer

• regression from LG-AIN to no AIN

• regression from high-grade to LG-AIN.

The estimation of these parameters is discussed in the following sections, as well as in the model calibration section.

Data sources for incidence and progression up to HG-AIN

Two studies, published in the mid- to late 1990s, inform parameter estimates of the natural history of anal cancer in HIV-negative and positive homosexual men. 57,61,70,89 Other studies were excluded on account of the absence of any histological follow-up, for example Sayers et al. 90 report a study based in Edinburgh, which followed up 20 HIV-positive men with dyskaryosis that was suggestive of AIN.

Critchlow et al. 89 undertook a prospective study beginning in January 1991, which followed 158 HIV-positive and 147 HIV-negative men in Seattle, Washington. This study excluded men with any positive cytology at baseline. Figure 4 describes the pathway to the final study sample. The mean follow-ups were 20.2 and 22.1 months for HIV-negative and positive men, respectively.

FIGURE 4.

Seattle study: pathway to study sample.

The other main study recruited a prospective cohort of homosexual and bisexual men in San Francisco between November 1991 and March 1994. 57,61 Analyses from the study are presented after 2-year70 and 4-year follow-up57 periods. The pathways to inclusion for these two analyses are presented in Figures 5 and 6.

FIGURE 5.

San Francisco study, 2-year analysis: pathway to study sample.

FIGURE 6.

San Francisco study, 4-year analysis: pathway to study sample.

Anal screening test and clinical presentation parameters

Parameters associated with the process of clinical diagnosis, leading to potential treatment are described in the following sections.

Costs

Cost inputs to the anal cancer screening model include the cost of screening, costs of diagnosis of precancerous AIN lesions, costs of diagnosis of anal cancer, and costs of treating diagnosed anal cancer. The estimation of these parameters is described in the following sections.

Utility values

In their study of screening for HIV-positive MSM, Goldie et al. 82 estimated a constant utility weight of 0.56 for individuals with AIDS and AIDS-related cancer. These estimates were derived from a rating scale valuation undertaken by patients (sample not given), and the subsequent Torrance transformation of rating scale valuations.

In the study of HIV-negative men, Goldie et al. 81 applied a quality adjustment weight of 0.60 (range 0.17 to 0.79) for individuals with anal cancer, which was based on utility weights reported for gastrointestinal cancer.

The utility weights applied by Goldie et al. 81 for anal cancer are comparable with utility estimates for metastatic disease in other cancers (e.g. breast cancer102), and so applying these weights to all cancer patients may overestimate the utility effects of anal cancer. However, in the absence of alternative data sources, a same approach to representing the utility effects of anal cancer in HIV-positive and HIV-negative men was used in the current study.

The utility decrements were applied to both diagnosed and undiagnosed individuals. This application accounts for the likelihood that undiagnosed patients may have slightly higher utility than diagnosed patients, but that later diagnosed patients may have lower utility during their treatment period due to less later treatment being less effective in reducing symptoms (or increased symptoms due to more aggressive treatment).

Estimates of the utility impact of HIV infection were sourced from a number of studies that reported patient-based elicitation of utility values, as presented in Table 28. The weights reported by Mauskopf et al. 103 are lower than the other three studies, which all present similar weights by CD4 count category. To maintain comparability, the utility weights reported by Goldie et al. 81 were used in the current model.

Goldie et al. 81 used the same process to estimate a utility value for patients receiving treatment for HG-AIN lesions of 0.98. In the current study, a utility multiplier was specified for the HG-AIN state, which was applied to relevant HIV-negative and HIV-positive states in cycles where patients received treatment for HG-AIN. The final parameter values for the utility parameters are presented in Table 29, which were represented as triangular distributions in the model.

Calibration outputs

The anal cancer screening model was calibrated to age-specific estimates of the incidence of anal cancer in the year 2003 as reported by the Cancer Registries,2 which should reflect the impact of HAART on incidence rates in HIV-positive individuals. Some adjustments were made to the presented incidence estimates to account for the completeness of the registry data.

Forman106 investigated the completeness of incident cases of skin cancer in Yorkshire recorded by the regional cancer registry in 1994. Patients diagnosed with skin cancer were identified from four independent information sources (pathology laboratories, outpatient clinics, general practices and the NHS Trust’s Information Services for information on patients who received inpatient care), which were then cross-checked against the regional cancer register. In total, the cancer registry registered 83.5% of all patients with skin cancer identified across the region.

Silcocks and Waterhouse107 applied the Flow method to patients diagnosed with cancer in 1996. For all cancers, completeness was 87.2% by 1 year and 92.3% by 5 years. Completeness was greater, and increased more quickly, for rapidly fatal cancers, with 1- and 5-year values of 96.4% and 97.3% (lung), and 95.3% and 96.5% (stomach) compared with 77.3% and 89.1% (female breast) and 76.9% and 88.8% (prostate). Colorectal cancers were an intermediate case (86.3% and 91.8%).

Based on the findings of the above two studies, and the fact that anal cancer appears to be a relatively slow progressing cancer, it was assumed that the cancer registry estimates for anal cancer had 77% completeness. The estimated numbers of cancers in each age group were, therefore, multiplied by 1.3 (1/0.77) to account for the missing cases.

The reported age-specific incidence rates were represented by beta distributions informed by the adjusted number of observed cases and the respective populations at risk, as presented in Table 30.

To estimate anal cancer incidence rates in the MSM population, it was necessary to define RRs of anal cancer for HIV-positive and HIV-negative MSM (compared with non-MSM). Age-specific anal cancer incidence rates in the non-MSM, and HIV-negative and HIV-positive MSM populations were then fitted to the observed aggregate anal cancer incidence rates for iteratively sampled RRs for each group, and the sizes of the respective groups.

Lampinen et al. 33 reference RRs of anal cancer among HIV-negative and HIV-positive MSM of 35 and 70, respectively. They also state that recent studies suggest that incidence rates among HIV-positive MSM may have further doubled, owing to increased survival since 1996 among men receiving potent antiretroviral treatment. A UK cohort study of 8640 HIV-positive individuals found the incidence of invasive anal cancer (diagnosed in 26 patients) to be 92 (95% CI 52 to 149) per 100,000 patient-years of follow-up in the post-HAART era (1996–2003),23 a mean RR of 176 compared with the general population.

Based on these studies, the calibration process assumed a mean RR for HIV-negative MSM of 35 (with a subjectively defined 95% CI 25 to 45). The RR for HIV-positive men was taken directly from the UK study (mean 176, 95% CI 99 to 285). Random values for these parameters were sampled from log-normal distributions.

Frisch et al. 13 estimated RRs for the incidence of invasive anal cancers in AIDS patients by age. They found elevated risks, particularly among patients under the age of 30 years, as shown in Table 31. Age-specific RRs for HIV-negative and HIV-positive MSMs were fitted to the respective sampled aggregate values, and the age-specific RRs (i.e. the age-specific RRs were fitted such that the relationship between the age-specific RRs was as estimated by Frisch, and the weighted aggregate RR equalled the sampled aggregate RR).

Age-specific estimates of the size of the MSM HIV-positive population were sampled from Poisson distributions informed by the data provided by the HPA, which were used to estimate the incidence of HIV in the MSM population (as described in Chapter 5, HIV incidence and progression in MSM). The sizes of the HIV-negative MSM populations were estimated by subtracting the sampled HIV-positive MSM population sizes from age-specific estimates of the MSM populations (as described in Chapter 5, HIV incidence and progression in MSM). The size of the non-MSM population at risk was estimated by subtracting the estimated numbers of MSM from age-specific estimates of the male population, informed by UK life tables.

For a sampled set of RRs and age-specific population sizes (non-MSM, HIV-positive MSM and HIV-negative MSM), a calibration outputs model defined the relationship between the anal cancer incidence rates in the different populations. The model then fitted the incidence rate in the non-MSM populations so that the weighted incidence rates matched the sampled aggregate incidence rates. This process was repeated for 5000 iterations in order to represent the correlated uncertainty around the age-specific incidence rates in HIV-negative and positive MSMs. The resulting estimates are presented in Table 32.

The model was also calibrated against the observed estimates of the prevalence of HIV-positive MSMs, as provided by the HPA and described in the HIV modelling section.

The calibration model

A separate model was developed to estimate model outputs for the year 2003 in the format of the calibration outputs described in the previous section. The calibration model commences in the year 1990, and runs separate analyses for individuals at the mid-point age of the six relevant age groups (15–25, 26–35, 36–45, 46–55, 56–65 and 66–75) from either the year in which they became 15 years old (i.e. 1998 for individuals aged 20 in the year 2003) or from 1990 at the age they were at the start of 1990 (e.g. 16 years for 30-year-olds in 2003).

Age groups aged over 15 years in 1990 were distributed between the ‘HIV negative, no anal lesions’ and the ‘HIV negative, undiagnosed HG-AIN’ states in the year 1990. The probability of having HG-AIN was informed by a simple submodel that estimated the progression of HIV-negative MSM from normal to HG-AIN (either directly or via LG-AIN) from an assumed incident MSM age of 26 years (using the transition probabilities for HIV-negative MSM described in Chapter 1, Incidence rate by age and gender).

Thus, the calibration model makes the following assumptions:

1. No MSMs who were HIV positive prior to 1990 remain alive in 2003.

2. Transition probabilities have remained constant between 1990 and 2003 (i.e. probabilities vary by age but not by calendar year)

It is recognised that neither of the above assumptions are likely to be true, although they bias the model in opposite directions. Assumption 1 decreases estimated cases of anal cancer, while the introduction of HAART in the mid-1990s is likely to have increased the incidence of anal cancer, so assuming that HAART influenced transition probabilities in the early 1990s will compensate the impact of assumption 1 to some degree.

For each of 2000 sets of input parameter values, the calibration model collected the age-specific incident rates of anal cancer in HIV-negative, and HIV-positive MSMs in 2003.

To account for slight bias due to the use of the mid-point age of each age group, the mean MSM rate was estimated as the mean proportion of each age group (in 2003) that were MSM during the preceding 13 years. In each age group, the mean MSM rate is compared with the proportion of MSM in the mid-point age for the age group, as those were the ages on which the calibration model is based. The ratio of the mean MSM rate to the MSM rate in the mid-point age for each age group was used to adjust the calibration estimates by multiplying the respective model outputs by this ratio.

Calibration data analysis

A two-stage calibration process was adopted. The first stage applied a threshold in which the predicted aggregate incidence rate of anal cancer was compared with the 95% CI for the aggregate incidence rate as estimated using the Cancer Registry data (described in Chapter 5, Anal cancer screening model structure).

The corresponding predicted estimates of the aggregate incidence of anal cancer in MSM, and in MSM by HIV status are presented in Table 32. The calibration threshold analysis found that 1719 of the 2000 input parameter sets estimated aggregate incidence rates within the 95% CIs. The comparison of the observed and predicted incidence rates (and 95% CIs) shows a close relationship.

The second stage of the calibration analysis involved estimating the sum of differences between the 1719 predicted output parameter values and the anal cancer incidence rate 95% CIs, by age group and HIV status. Table 33 presents the observed and predicted ranges for each incidence category. The results show that extremely small numbers are expected in the early age groups, such that the differences between the observed and predicted incidence in these groups had minimal impact on the cost-effectiveness results. The overlap between the predicted and observed incidence in the other age categories is encouraging.

The following stages informed the assignment of sampling probabilities to each of the eligible input parameters:

1. Sum of differences between each age- and HIV status-specific incidence estimate and the bounds of the respective observed 95% CIs were calculated for each iteration.

2. Proportions of the sum of differences contributed by each input parameter set were estimated.

3. Reciprocals of the proportions of the sum of differences contributed by each iteration were estimated (no iterations had a sum of differences of zero).

4. Reciprocals were divided by the sum of the reciprocals to estimate the probability that each of the 1719 parameter sets was the most relevant set.

Anal cancer screening model analysis

Following the calibration process, and the identification and ranking of eligible input parameter sets, the model was analysed to estimate the costs and QALYs associated with 10 alternative screening programmes as well as a no screening option. The 10 programmes included five programmes for HIV-positive MSM only, and five programmes for all MSM. Screening intervals of 1, 2, 3, 4 and 5 years were analysed for both eligible populations.

The starting states for each age group (i.e. the distribution of each population across model’s states in 2003) were informed by the calibration model that recorded the finishing states of each population for each input parameter set at the end of the calibration period (i.e. the year 2003). The model analysed each age group to a maximum age of 100 years and then combined the discounted (at 3.5% per annum) costs and effects for each age group on the basis of the respective proportions of the total person-years represented within the full model time horizon.

The reference case analysis involved the random sampling of 2000 sets of input parameter sets based on the ranking probabilities estimated as part of the calibration process. Additional analyses were undertaken in which the following assumptions were tested:

• no utility effects associated with false-positives or treatment for HG-AIN

• increasing the regression rates for individuals with LG-AIN lesions returning to having no AIN lesion.

Reference case cost-effectiveness results

The mean results from the reference case analysis of the model are presented in Table 34, which show that screening is actually more costly and less effective than providing no screening, i.e. no screening dominates screening for either HIV-positive MSM alone or all MSM. The reduced number of QALYs gained is due to the utility decrements associated with false-positive screening results, and the treatment effects of HG-AIN.

Calculations were undertaken to inform the cost-effectiveness acceptability frontier, which describes the probability that the screening option with the highest expected net benefits is the most cost-effective option. These estimates show that no screening has the highest expected net benefits and is 100% certain (given the reference case model, inputs and assumptions) to be the most cost-effective option, to a value of a QALY of £50,000.

Sensitivity analyses

In addition to the probabilistic sensitivity analysis reported above, additional sensitivity analyses were undertaken around the most uncertain input parameters. The estimates of anal cancer incidence used to calibrate the model were not excessively uncertain, and conservative assumptions had been implemented, for example a low completeness rate was assumed for the cancer registry data, and high estimates of the RRs for HIV-positive and HIV-negative MSM developing anal cancer were specified. Thus, anal cancer incidence in high-risk groups was not a key parameter for investigation.

Additional sensitivity analyses tested the impact of assuming that the effects of investigation following false-positive screen results and treatment for HG-AIN incurred no utility decrements. The mean results of this analysis are presented in Table 35, which show that the screening programmes for diagnosed HIV-positive individuals are now shown to be more effective than no screening, although the minimum incremental cost per QALY gained (ICQ) is almost £66,000. The ICQs for screening for all MSM drop to £50,000, but remain well above accepted cost-effectiveness thresholds. The related cost-effectiveness acceptability frontier is presented in Figure 7. This shows that no screening retains a very high probability of being the most cost-effective option, with the highest mean net benefits to a QALY value of £50,000.

FIGURE 7.

Cost-effectiveness acceptability frontier assuming no utility decrement from false-positive screen results or treatment for high-grade anal intraepithelial neoplasia. NB, net benefit.

Another uncertain parameter was the rate of regression of LG-AIN, which had been informed by the two main cohort studies of MSM and anal cancer. 57,61,70,89 However, Goldie et al. 81 had estimated higher regression rates, which may impact on cost-effectiveness by increasing the likelihood of progression from HG-AIN to anal cancer. The calibration model was re-run incorporating revised annual probabilities of regression from LG-AIN to no AIN (30% in HIV-negative MSM, 15% in HIV-positive MSM with CD4 count > 500, 10% with CD4 count 200–500, and 5% with CD4 count < 200), which were fitted to observed anal cancer incidence rates by altering the transition probability between HG-AIN and anal cancer. Recalibrating the model required increasing the HG-AIN to anal cancer rates by 22%.

Table 36 presents the mean results from the combining increased AIN regression rates with no utility decrements from screening, which show that the minimum ICQ from implementing any of the screening programmes for MSM is reduced to £44,656. Screening all MSM is shown to be more effective than screening HIV-positive MSM due to gains from the early detection of undiagnosed HIV-positive MSM as a result of screening for anal cancer.

The cost-effectiveness acceptability frontier (Figure 8) shows that no screening has the highest mean net benefits to a value of a QALY of £45,000 with the probability of no screening being the most cost-effective option remaining above 50%. At higher QALY values, screening programmes for all MSM have higher expected net benefits, although no screening retains a probability of cost-effectiveness of over 50% to a QALY value of £50,000.

FIGURE 8.

Cost-effectiveness acceptability frontier assuming increased anal intraepithelial neoplasia (AIN) regression and no utility decrement from false-positive screen results or treatment for high-grade AIN. NB, net benefit.

Model population and calibration

A key aspect of the female HIV-positive screening model was that incidence of AIN in HIV-negative women is negligible, and assumed to be zero. As in the MSM model, the women’s model includes HIV-negative individuals in order to describe the incidence of HIV-positive women over time, but all incident HIV-positive women enter the ‘CD4 count > 500’ state without AIN.

Fewer data were available from the literature to populate parameters for the HIV-positive women screening model, for example no longitudinal data describing AIN progression in HIV-positive women were identified. Indeed, the only female-specific data included estimates of age-specific HIV incidence, and the data required to estimate the calibration output parameters (age-specific anal cancer incidence). All other parameters were informed by data collected to populate the MSM screening model, although a separate calibration process was undertaken for the female screening model.

Unlike men, incidence rates of HIV infection in women have varied significantly over time, with low rates in the early 1990s (around 500 per year), rising to a peak in 2003 (3251) and then falling back to 2283 in 2007. 108 Thus, separate HIV incidence rates were defined for the years 1992–2000 and 2002–7 for the calibration model, while the latter incidence rates were used in the main analysis model.

The model was calibrated to age-specific numbers of anal cancers occurring in HIV-positive women (the calibration outputs), which were estimated using the following data:

• age-specific estimates of anal cancer incidence in women in 2005 (uprated to allow for under registration)2

• relative risk of anal cancer in HIV-positive women (6.8, 95% CI 2.7 to 14)13

• age-related RRs of anal cancer in HIV-positive women (e.g. RR of anal cancer in HIV women aged under 30 years, 30–39 years, etc.), informed by a study of HIV-associated anogenital cancers by age at onset of AIDS13

• prevalence of diagnosed HIV women in 2005 (converted to age-specific numbers assuming a similar proportional split to HIV-positive males)109

• prevalence of undiagnosed HIV women, based on observation that 33.7% of all HIV-positive individuals in the UK were undiagnosed in 2004 (assumed to have the same age distribution as diagnosed HIV women). 110

Age-specific anal cancer incidence in HIV-positive women in 2005 was estimated using an adjusted version of the calibration outputs model described for MSM in Chapter 6. The model estimated the incidence rates in the HIV-positive female populations by sampling a set of parameter values describing the aggregate age-specific incidence of anal cancer in women, the aggregate RR of anal cancer in HIV-positive women, age-related RRs of anal cancer, and the size of the HIV-positive female population. For a sampled set of values, the model defined the relationship between the incidence rates for the HIV-positive and HIV-negative populations using the sampled RRs. The model then fitted the incidence rate in the HIV-negative population so that the weighted age-specific anal cancer incidence rates (based on the sampled sizes of the respective populations) matched the sampled aggregate incidence rate. This process was repeated for 2000 iterations in order to represent the correlated uncertainty around the age-specific incidence rates in HIV-negative and HIV-positive women. The resulting estimates are presented in Table 37.

Table 37 shows that the calibration results obtained from applying the same AIN incidence and progression parameter values, as fitted for the MSM model, overestimated the rate of anal cancer in HIV-positive women. To the clinical authors’ knowledge, there is no known biological reason that AIN would progress differently in HIV-positive men and HIV-positive women, but one might expect AIN incidence to be lower in HIV-positive women than in HIV-positive MSM. Therefore, the model was recalibrated, keeping the same AIN progression parameters as estimated for the MSM model, but lowering AIN incidence until a good fit was achieved with the estimated anal cancer incidence rates (in HIV-positive women). This was achieved when HIV-positive MSM AIN incidence rates were reduced by 67%, and all 2000 iterations estimated rates within the 95% CI for the observed rates. Estimated AIN incidence rates across the eligible populations are compared in Table 38.

The second stage of the calibration analysis involved estimating the sum of differences between the 2000 predicted output parameter values and the anal cancer incidence rate (95% CIs) by age group. Table 39 presents the observed and predicted ranges for each incidence category. The results show that the ranges for the observed and expected data are an extremely good fit, which is encouraging.

Anal cancer screening model analysis

The model was analysed to estimate the costs and QALYs associated with programmes for HIV-positive women with screening intervals of 1, 2, 3, 4 and 5 years. The starting states for each age group (i.e. the distribution of each population across model’s states in 2003) were informed by the calibration model that recorded the finishing states of each population for each input parameter set at the end of the calibration period (i.e. the year 2003). The model analysed each age group to a maximum age of 100 years, and then combined the discounted costs and effects (at 3.5% per annum) for each age group on the basis of the respective proportions of the total person-years represented within the full model time horizon.

The reference case analysis involved the random sampling of 2000 sets of input parameter sets, based on the ranking probabilities estimated as part of the calibration process. Additional analyses were undertaken in which the following assumptions were tested:

• no utility effects associated with false-positives or treatment for HG-AIN

• increasing the regression rates for individuals with LG-AIN lesions and returning to having no AIN lesion.

Results

The mean results from the reference case analysis of the model are presented in Table 40. As for MSM, screening HIV-positive women is more costly and less effective than providing no screening, i.e. no screening dominates screening. The reduced number of QALYs gained is due to the utility decrements associated with false-positive screening results, and the treatment effects of HG-AIN.

Calculations were undertaken to inform the cost-effectiveness acceptability frontier, which describes the probability that the screening option with the highest expected net benefits is the most cost-effective option. These estimates show that no screening has the highest expected net benefits and is 100% certain (given the reference case model, inputs and assumptions) to be the most cost-effective option, to a value of a QALY of £50,000.

Sensitivity analyses

Additional sensitivity analyses tested the impact of assuming that the effects of investigation following false-positive screen results and treatment for HG-AIN incurred no utility decrements. The mean results of this analysis are presented in Table 41, which show that the screening programmes for diagnosed HIV-positive women are now shown to be more effective than no screening, although the minimum ICQ is £88,247. Data to inform the related cost-effectiveness acceptability frontier shows that no screening retains a 100% probability of being the most cost-effective option, with the highest expected net benefits to a QALY value of £50,000. Increasing regression rates from LG-AIN had little further effect on the ICQs for screening HIV-positive women.

The systematic review

Limited information is available from published research about the potential impact of anal cancer screening of high-risk groups. The limitations are from the study designs used, as well as the quality of reporting of the studies.

The main role of the screening studies27,28,30,31,34,35 included in the report is in assessing whether the screening test performance is adequate to justify the establishment of an anal cancer screening programme. Not all the studies gave completeness of the information.

In their systematic review of anal Pap smear screening for HIV-infected patients, Chiao et al. 36 reported that the data published highlight limitations to current anal Pap smear screening-related research, with no randomised or cohort studies existing to determine if there are improved survival or outcomes for those who have been screened.

The NSC1 has produced a modified version of the World Health Organization (WHO) screening criteria to take into account the more rigorous standards of evidence, as well as to increase the weight given to the potential negative effects of screening. The document states that all the criteria should be satisfied before a screening programme is introduced.

The NSC1 criteria (where applicable) are outlined below, and are commented on with reference to anal cancer screening.

The cost-effectiveness model

Contribution of the authors

Jon Karnon undertook the cost-effectiveness reviewing, constructed the model and prepared those sections of the draft report. Carolyn Czoski-Murray undertook sections of the reviewing and preparation of the draft report. Roy Jones was the main reviewer and prepared sections of the draft report. Kevin Smith assisted with the selection of papers relevant to a screening model, and provided expert advice on the appropriate assumptions of the screening model and preparation of the draft report. George Kinghorn assisted with the selection of papers and the impact on the genitourinary medicine services, and contributed to the draft report.

Ed Levine, although not listed as a co-author, was a clinician at the Christie Hospital, Manchester, and provided clinical advice on the population of interest to the review and advised on the selection of clinical trials of relevance to the screening model.

Marc Chattle, School of Health and Related Research, University of Sheffield, provided administrative and clerical support in the formatting of the draft report.

Disclaimers

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Ideally, all of the following criteria should be met before screening for a condition is initiated.

Health Technology Assessment reports published to date

1. Home parenteral nutrition: a systematic review.

   By Richards DM, Deeks JJ, Sheldon TA, Shaffer JL.

2. Diagnosis, management and screening of early localised prostate cancer.

   A review by Selley S, Donovan J, Faulkner A, Coast J, Gillatt D.

3. The diagnosis, management, treatment and costs of prostate cancer in England and Wales.

   A review by Chamberlain J, Melia J, Moss S, Brown J.

4. Screening for fragile X syndrome.

   A review by Murray J, Cuckle H, Taylor G, Hewison J.

5. A review of near patient testing in primary care.

   By Hobbs FDR, Delaney BC, Fitzmaurice DA, Wilson S, Hyde CJ, Thorpe GH, et al.

6. Systematic review of outpatient services for chronic pain control.

   By McQuay HJ, Moore RA, Eccleston C, Morley S, de C Williams AC.

7. Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

   A review by Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ, Leonard JV, et al.

8. Preschool vision screening.

   A review by Snowdon SK, Stewart-Brown SL.

9. Implications of socio-cultural contexts for the ethics of clinical trials.

   A review by Ashcroft RE, Chadwick DW, Clark SRL, Edwards RHT, Frith L, Hutton JL.

10. A critical review of the role of neonatal hearing screening in the detection of congenital hearing impairment.

    By Davis A, Bamford J, Wilson I, Ramkalawan T, Forshaw M, Wright S.

11. Newborn screening for inborn errors of metabolism: a systematic review.

    By Seymour CA, Thomason MJ, Chalmers RA, Addison GM, Bain MD, Cockburn F, et al.

12. Routine preoperative testing: a systematic review of the evidence.

    By Munro J, Booth A, Nicholl J.

13. Systematic review of the effectiveness of laxatives in the elderly.

    By Petticrew M, Watt I, Sheldon T.

14. When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.

    A review by Mowatt G, Bower DJ, Brebner JA, Cairns JA, Grant AM, McKee L.

1. Antenatal screening for Down’s syndrome.

   A review by Wald NJ, Kennard A, Hackshaw A, McGuire A.

2. Screening for ovarian cancer: a systematic review.

   By Bell R, Petticrew M, Luengo S, Sheldon TA.

3. Consensus development methods, and their use in clinical guideline development.

   A review by Murphy MK, Black NA, Lamping DL, McKee CM, Sanderson CFB, Askham J, et al.

4. A cost–utility analysis of interferon beta for multiple sclerosis.

   By Parkin D, McNamee P, Jacoby A, Miller P, Thomas S, Bates D.

5. Effectiveness and efficiency of methods of dialysis therapy for end-stage renal disease: systematic reviews.

   By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M, Daly C, et al.

6. Effectiveness of hip prostheses in primary total hip replacement: a critical review of evidence and an economic model.

   By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M, Bevan G.

7. Antimicrobial prophylaxis in colorectal surgery: a systematic review of randomised controlled trials.

   By Song F, Glenny AM.

8. Bone marrow and peripheral blood stem cell transplantation for malignancy.

   A review by Johnson PWM, Simnett SJ, Sweetenham JW, Morgan GJ, Stewart LA.

9. Screening for speech and language delay: a systematic review of the literature.

   By Law J, Boyle J, Harris F, Harkness A, Nye C.

10. Resource allocation for chronic stable angina: a systematic review of effectiveness, costs and cost-effectiveness of alternative interventions.

    By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR, Buxton MJ.

11. Detection, adherence and control of hypertension for the prevention of stroke: a systematic review.

    By Ebrahim S.

12. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review.

    By McQuay HJ, Moore RA.

13. Choosing between randomised and nonrandomised studies: a systematic review.

    By Britton A, McKee M, Black N, McPherson K, Sanderson C, Bain C.

14. Evaluating patient-based outcome measures for use in clinical trials.

    A review by Fitzpatrick R, Davey C, Buxton MJ, Jones DR.

15. Ethical issues in the design and conduct of randomised controlled trials.

    A review by Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J.

16. Qualitative research methods in health technology assessment: a review of the literature.

    By Murphy E, Dingwall R, Greatbatch D, Parker S, Watson P.

17. The costs and benefits of paramedic skills in pre-hospital trauma care.

    By Nicholl J, Hughes S, Dixon S, Turner J, Yates D.

18. Systematic review of endoscopic ultrasound in gastro-oesophageal cancer.

    By Harris KM, Kelly S, Berry E, Hutton J, Roderick P, Cullingworth J, et al.

19. Systematic reviews of trials and other studies.

    By Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F.

20. Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses.

    A review by Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, et al.

1. Informed decision making: an annotated bibliography and systematic review.

   By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J, Robinson MB, et al.

2. Handling uncertainty when performing economic evaluation of healthcare interventions.

   A review by Briggs AH, Gray AM.

3. The role of expectancies in the placebo effect and their use in the delivery of health care: a systematic review.

   By Crow R, Gage H, Hampson S, Hart J, Kimber A, Thomas H.

4. A randomised controlled trial of different approaches to universal antenatal HIV testing: uptake and acceptability. Annex: Antenatal HIV testing – assessment of a routine voluntary approach.

   By Simpson WM, Johnstone FD, Boyd FM, Goldberg DJ, Hart GJ, Gormley SM, et al.

5. Methods for evaluating area-wide and organisation-based interventions in health and health care: a systematic review.

   By Ukoumunne OC, Gulliford MC, Chinn S, Sterne JAC, Burney PGJ.

6. Assessing the costs of healthcare technologies in clinical trials.

   A review by Johnston K, Buxton MJ, Jones DR, Fitzpatrick R.

7. Cooperatives and their primary care emergency centres: organisation and impact.

   By Hallam L, Henthorne K.

8. Screening for cystic fibrosis.

   A review by Murray J, Cuckle H, Taylor G, Littlewood J, Hewison J.

9. A review of the use of health status measures in economic evaluation.

   By Brazier J, Deverill M, Green C, Harper R, Booth A.

10. Methods for the analysis of quality-of-life and survival data in health technology assessment.

    A review by Billingham LJ, Abrams KR, Jones DR.

11. Antenatal and neonatal haemoglobinopathy screening in the UK: review and economic analysis.

    By Zeuner D, Ades AE, Karnon J, Brown J, Dezateux C, Anionwu EN.

12. Assessing the quality of reports of randomised trials: implications for the conduct of meta-analyses.

    A review by Moher D, Cook DJ, Jadad AR, Tugwell P, Moher M, Jones A, et al.

13. ‘Early warning systems’ for identifying new healthcare technologies.

    By Robert G, Stevens A, Gabbay J.

14. A systematic review of the role of human papillomavirus testing within a cervical screening programme.

    By Cuzick J, Sasieni P, Davies P, Adams J, Normand C, Frater A, et al.

15. Near patient testing in diabetes clinics: appraising the costs and outcomes.

    By Grieve R, Beech R, Vincent J, Mazurkiewicz J.

16. Positron emission tomography: establishing priorities for health technology assessment.

    A review by Robert G, Milne R.

17. The debridement of chronic wounds: a systematic review.

    By Bradley M, Cullum N, Sheldon T.

18. Systematic reviews of wound care management: (2) Dressings and topical agents used in the healing of chronic wounds.

    By Bradley M, Cullum N, Nelson EA, Petticrew M, Sheldon T, Torgerson D.

19. A systematic literature review of spiral and electron beam computed tomography: with particular reference to clinical applications in hepatic lesions, pulmonary embolus and coronary artery disease.

    By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

20. What role for statins? A review and economic model.

    By Ebrahim S, Davey Smith G, McCabe C, Payne N, Pickin M, Sheldon TA, et al.

21. Factors that limit the quality, number and progress of randomised controlled trials.

    A review by Prescott RJ, Counsell CE, Gillespie WJ, Grant AM, Russell IT, Kiauka S, et al.

22. Antimicrobial prophylaxis in total hip replacement: a systematic review.

    By Glenny AM, Song F.

23. Health promoting schools and health promotion in schools: two systematic reviews.

    By Lister-Sharp D, Chapman S, Stewart-Brown S, Sowden A.

24. Economic evaluation of a primary care-based education programme for patients with osteoarthritis of the knee.

    A review by Lord J, Victor C, Littlejohns P, Ross FM, Axford JS.

1. The estimation of marginal time preference in a UK-wide sample (TEMPUS) project.

   A review by Cairns JA, van der Pol MM.

2. Geriatric rehabilitation following fractures in older people: a systematic review.

   By Cameron I, Crotty M, Currie C, Finnegan T, Gillespie L, Gillespie W, et al.

3. Screening for sickle cell disease and thalassaemia: a systematic review with supplementary research.

   By Davies SC, Cronin E, Gill M, Greengross P, Hickman M, Normand C.

4. Community provision of hearing aids and related audiology services.

   A review by Reeves DJ, Alborz A, Hickson FS, Bamford JM.

5. False-negative results in screening programmes: systematic review of impact and implications.

   By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

6. Costs and benefits of community postnatal support workers: a randomised controlled trial.

   By Morrell CJ, Spiby H, Stewart P, Walters S, Morgan A.

7. Implantable contraceptives (subdermal implants and hormonally impregnated intrauterine systems) versus other forms of reversible contraceptives: two systematic reviews to assess relative effectiveness, acceptability, tolerability and cost-effectiveness.

   By French RS, Cowan FM, Mansour DJA, Morris S, Procter T, Hughes D, et al.

8. An introduction to statistical methods for health technology assessment.

   A review by White SJ, Ashby D, Brown PJ.

9. Disease-modifying drugs for multiple sclerosis: a rapid and systematic review.

   By Clegg A, Bryant J, Milne R.

10. Publication and related biases.

    A review by Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ.

11. Cost and outcome implications of the organisation of vascular services.

    By Michaels J, Brazier J, Palfreyman S, Shackley P, Slack R.

12. Monitoring blood glucose control in diabetes mellitus: a systematic review.

    By Coster S, Gulliford MC, Seed PT, Powrie JK, Swaminathan R.

13. The effectiveness of domiciliary health visiting: a systematic review of international studies and a selective review of the British literature.

    By Elkan R, Kendrick D, Hewitt M, Robinson JJA, Tolley K, Blair M, et al.

14. The determinants of screening uptake and interventions for increasing uptake: a systematic review.

    By Jepson R, Clegg A, Forbes C, Lewis R, Sowden A, Kleijnen J.

15. The effectiveness and cost-effectiveness of prophylactic removal of wisdom teeth.

    A rapid review by Song F, O’Meara S, Wilson P, Golder S, Kleijnen J.

16. Ultrasound screening in pregnancy: a systematic review of the clinical effectiveness, cost-effectiveness and women’s views.

    By Bricker L, Garcia J, Henderson J, Mugford M, Neilson J, Roberts T, et al.

17. A rapid and systematic review of the effectiveness and cost-effectiveness of the taxanes used in the treatment of advanced breast and ovarian cancer.

    By Lister-Sharp D, McDonagh MS, Khan KS, Kleijnen J.

18. Liquid-based cytology in cervical screening: a rapid and systematic review.

    By Payne N, Chilcott J, McGoogan E.

19. Randomised controlled trial of non-directive counselling, cognitive–behaviour therapy and usual general practitioner care in the management of depression as well as mixed anxiety and depression in primary care.

    By King M, Sibbald B, Ward E, Bower P, Lloyd M, Gabbay M, et al.

20. Routine referral for radiography of patients presenting with low back pain: is patients’ outcome influenced by GPs’ referral for plain radiography?

    By Kerry S, Hilton S, Patel S, Dundas D, Rink E, Lord J.

21. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration.

    By O’Meara S, Cullum N, Majid M, Sheldon T.

22. Using routine data to complement and enhance the results of randomised controlled trials.

    By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

23. Coronary artery stents in the treatment of ischaemic heart disease: a rapid and systematic review.

    By Meads C, Cummins C, Jolly K, Stevens A, Burls A, Hyde C.

24. Outcome measures for adult critical care: a systematic review.

    By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM, Daly K, et al.

25. A systematic review to evaluate the effectiveness of interventions to promote the initiation of breastfeeding.

    By Fairbank L, O’Meara S, Renfrew MJ, Woolridge M, Sowden AJ, Lister-Sharp D.

26. Implantable cardioverter defibrillators: arrhythmias. A rapid and systematic review.

    By Parkes J, Bryant J, Milne R.

27. Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

    By Brañas P, Jordan R, Fry-Smith A, Burls A, Hyde C.

28. Early asthma prophylaxis, natural history, skeletal development and economy (EASE): a pilot randomised controlled trial.

    By Baxter-Jones ADG, Helms PJ, Russell G, Grant A, Ross S, Cairns JA, et al.

29. Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

    By Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HAW.

30. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists in the medical management of unstable angina.

    By McDonagh MS, Bachmann LM, Golder S, Kleijnen J, ter Riet G.

31. A randomised controlled trial of prehospital intravenous fluid replacement therapy in serious trauma.

    By Turner J, Nicholl J, Webber L, Cox H, Dixon S, Yates D.

32. Intrathecal pumps for giving opioids in chronic pain: a systematic review.

    By Williams JE, Louw G, Towlerton G.

33. Combination therapy (interferon alfa and ribavirin) in the treatment of chronic hepatitis C: a rapid and systematic review.

    By Shepherd J, Waugh N, Hewitson P.

34. A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

    By MacLehose RR, Reeves BC, Harvey IM, Sheldon TA, Russell IT, Black AMS.

35. Intravascular ultrasound-guided interventions in coronary artery disease: a systematic literature review, with decision-analytic modelling, of outcomes and cost-effectiveness.

    By Berry E, Kelly S, Hutton J, Lindsay HSJ, Blaxill JM, Evans JA, et al.

36. A randomised controlled trial to evaluate the effectiveness and cost-effectiveness of counselling patients with chronic depression.

    By Simpson S, Corney R, Fitzgerald P, Beecham J.

37. Systematic review of treatments for atopic eczema.

    By Hoare C, Li Wan Po A, Williams H.

38. Bayesian methods in health technology assessment: a review.

    By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

39. The management of dyspepsia: a systematic review.

    By Delaney B, Moayyedi P, Deeks J, Innes M, Soo S, Barton P, et al.

40. A systematic review of treatments for severe psoriasis.

    By Griffiths CEM, Clark CM, Chalmers RJG, Li Wan Po A, Williams HC.

1. Clinical and cost-effectiveness of donepezil, rivastigmine and galantamine for Alzheimer’s disease: a rapid and systematic review.

   By Clegg A, Bryant J, Nicholson T, McIntyre L, De Broe S, Gerard K, et al.

2. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review.

   By Stewart A, Sandercock J, Bryan S, Hyde C, Barton PM, Fry-Smith A, et al.

3. Equity and the economic evaluation of healthcare.

   By Sassi F, Archard L, Le Grand J.

4. Quality-of-life measures in chronic diseases of childhood.

   By Eiser C, Morse R.

5. Eliciting public preferences for healthcare: a systematic review of techniques.

   By Ryan M, Scott DA, Reeves C, Bate A, van Teijlingen ER, Russell EM, et al.

6. General health status measures for people with cognitive impairment: learning disability and acquired brain injury.

   By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

7. An assessment of screening strategies for fragile X syndrome in the UK.

   By Pembrey ME, Barnicoat AJ, Carmichael B, Bobrow M, Turner G.

8. Issues in methodological research: perspectives from researchers and commissioners.

   By Lilford RJ, Richardson A, Stevens A, Fitzpatrick R, Edwards S, Rock F, et al.

9. Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy.

   By Cullum N, Nelson EA, Flemming K, Sheldon T.

10. Effects of educational and psychosocial interventions for adolescents with diabetes mellitus: a systematic review.

    By Hampson SE, Skinner TC, Hart J, Storey L, Gage H, Foxcroft D, et al.

11. Effectiveness of autologous chondrocyte transplantation for hyaline cartilage defects in knees: a rapid and systematic review.

    By Jobanputra P, Parry D, Fry-Smith A, Burls A.

12. Statistical assessment of the learning curves of health technologies.

    By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF, Russell IT.

13. The effectiveness and cost-effectiveness of temozolomide for the treatment of recurrent malignant glioma: a rapid and systematic review.

    By Dinnes J, Cave C, Huang S, Major K, Milne R.

14. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of debriding agents in treating surgical wounds healing by secondary intention.

    By Lewis R, Whiting P, ter Riet G, O’Meara S, Glanville J.

15. Home treatment for mental health problems: a systematic review.

    By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

16. How to develop cost-conscious guidelines.

    By Eccles M, Mason J.

17. The role of specialist nurses in multiple sclerosis: a rapid and systematic review.

    By De Broe S, Christopher F, Waugh N.

18. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity.

    By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

19. The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review.

    By Chilcott J, Wight J, Lloyd Jones M, Tappenden P.

20. Extended scope of nursing practice: a multicentre randomised controlled trial of appropriately trained nurses and preregistration house officers in preoperative assessment in elective general surgery.

    By Kinley H, Czoski-Murray C, George S, McCabe C, Primrose J, Reilly C, et al.

21. Systematic reviews of the effectiveness of day care for people with severe mental disorders: (1) Acute day hospital versus admission; (2) Vocational rehabilitation; (3) Day hospital versus outpatient care.

    By Marshall M, Crowther R, Almaraz- Serrano A, Creed F, Sledge W, Kluiter H, et al.

22. The measurement and monitoring of surgical adverse events.

    By Bruce J, Russell EM, Mollison J, Krukowski ZH.

23. Action research: a systematic review and guidance for assessment.

    By Waterman H, Tillen D, Dickson R, de Koning K.

24. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer.

    By Ward S, Morris E, Bansback N, Calvert N, Crellin A, Forman D, et al.

25. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer.

    By Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M.

26. Comparison of the effectiveness of inhaler devices in asthma and chronic obstructive airways disease: a systematic review of the literature.

    By Brocklebank D, Ram F, Wright J, Barry P, Cates C, Davies L, et al.

27. The cost-effectiveness of magnetic resonance imaging for investigation of the knee joint.

    By Bryan S, Weatherburn G, Bungay H, Hatrick C, Salas C, Parry D, et al.

28. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of topotecan for ovarian cancer.

    By Forbes C, Shirran L, Bagnall A-M, Duffy S, ter Riet G.

29. Superseded by a report published in a later volume.

30. The role of radiography in primary care patients with low back pain of at least 6 weeks duration: a randomised (unblinded) controlled trial.

    By Kendrick D, Fielding K, Bentley E, Miller P, Kerslake R, Pringle M.

31. Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients.

    By McColl E, Jacoby A, Thomas L, Soutter J, Bamford C, Steen N, et al.

32. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine in non-small-cell lung cancer.

    By Clegg A, Scott DA, Sidhu M, Hewitson P, Waugh N.

33. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives.

    By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G.

34. Depot antipsychotic medication in the treatment of patients with schizophrenia: (1) Meta-review; (2) Patient and nurse attitudes.

    By David AS, Adams C.

35. A systematic review of controlled trials of the effectiveness and cost-effectiveness of brief psychological treatments for depression.

    By Churchill R, Hunot V, Corney R, Knapp M, McGuire H, Tylee A, et al.

36. Cost analysis of child health surveillance.

    By Sanderson D, Wright D, Acton C, Duree D.

1. A study of the methods used to select review criteria for clinical audit.

   By Hearnshaw H, Harker R, Cheater F, Baker R, Grimshaw G.

2. Fludarabine as second-line therapy for B cell chronic lymphocytic leukaemia: a technology assessment.

   By Hyde C, Wake B, Bryan S, Barton P, Fry-Smith A, Davenport C, et al.

3. Rituximab as third-line treatment for refractory or recurrent Stage III or IV follicular non-Hodgkin’s lymphoma: a systematic review and economic evaluation.

   By Wake B, Hyde C, Bryan S, Barton P, Song F, Fry-Smith A, et al.

4. A systematic review of discharge arrangements for older people.

   By Parker SG, Peet SM, McPherson A, Cannaby AM, Baker R, Wilson A, et al.

5. The clinical effectiveness and cost-effectiveness of inhaler devices used in the routine management of chronic asthma in older children: a systematic review and economic evaluation.

   By Peters J, Stevenson M, Beverley C, Lim J, Smith S.

6. The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment.

   By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

7. The cost-effectiveness of magnetic resonance angiography for carotid artery stenosis and peripheral vascular disease: a systematic review.

   By Berry E, Kelly S, Westwood ME, Davies LM, Gough MJ, Bamford JM, et al.

8. Promoting physical activity in South Asian Muslim women through ‘exercise on prescription’.

   By Carroll B, Ali N, Azam N.

9. Zanamivir for the treatment of influenza in adults: a systematic review and economic evaluation.

   By Burls A, Clark W, Stewart T, Preston C, Bryan S, Jefferson T, et al.

10. A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models.

    By Richards RG, Sampson FC, Beard SM, Tappenden P.

11. Screening for gestational diabetes: a systematic review and economic evaluation.

    By Scott DA, Loveman E, McIntyre L, Waugh N.

12. The clinical effectiveness and cost-effectiveness of surgery for people with morbid obesity: a systematic review and economic evaluation.

    By Clegg AJ, Colquitt J, Sidhu MK, Royle P, Loveman E, Walker A.

13. The clinical effectiveness of trastuzumab for breast cancer: a systematic review.

    By Lewis R, Bagnall A-M, Forbes C, Shirran E, Duffy S, Kleijnen J, et al.

14. The clinical effectiveness and cost-effectiveness of vinorelbine for breast cancer: a systematic review and economic evaluation.

    By Lewis R, Bagnall A-M, King S, Woolacott N, Forbes C, Shirran L, et al.

15. A systematic review of the effectiveness and cost-effectiveness of metal-on-metal hip resurfacing arthroplasty for treatment of hip disease.

    By Vale L, Wyness L, McCormack K, McKenzie L, Brazzelli M, Stearns SC.

16. The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.

    By Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, et al.

17. A systematic review of effectiveness and economic evaluation of new drug treatments for juvenile idiopathic arthritis: etanercept.

    By Cummins C, Connock M, Fry-Smith A, Burls A.

18. Clinical effectiveness and cost-effectiveness of growth hormone in children: a systematic review and economic evaluation.

    By Bryant J, Cave C, Mihaylova B, Chase D, McIntyre L, Gerard K, et al.

19. Clinical effectiveness and cost-effectiveness of growth hormone in adults in relation to impact on quality of life: a systematic review and economic evaluation.

    By Bryant J, Loveman E, Chase D, Mihaylova B, Cave C, Gerard K, et al.

20. Clinical medication review by a pharmacist of patients on repeat prescriptions in general practice: a randomised controlled trial.

    By Zermansky AG, Petty DR, Raynor DK, Lowe CJ, Freementle N, Vail A.

21. The effectiveness of infliximab and etanercept for the treatment of rheumatoid arthritis: a systematic review and economic evaluation.

    By Jobanputra P, Barton P, Bryan S, Burls A.

22. A systematic review and economic evaluation of computerised cognitive behaviour therapy for depression and anxiety.

    By Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G, Chilcott J.

23. A systematic review and economic evaluation of pegylated liposomal doxorubicin hydrochloride for ovarian cancer.

    By Forbes C, Wilby J, Richardson G, Sculpher M, Mather L, Riemsma R.

24. A systematic review of the effectiveness of interventions based on a stages-of-change approach to promote individual behaviour change.

    By Riemsma RP, Pattenden J, Bridle C, Sowden AJ, Mather L, Watt IS, et al.

25. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists.

    By Robinson M, Ginnelly L, Sculpher M, Jones L, Riemsma R, Palmer S, et al.

26. A systematic review of the effectiveness, cost-effectiveness and barriers to implementation of thrombolytic and neuroprotective therapy for acute ischaemic stroke in the NHS.

    By Sandercock P, Berge E, Dennis M, Forbes J, Hand P, Kwan J, et al.

27. A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in a bronchiectasis clinic.

    By Caine N, Sharples LD, Hollingworth W, French J, Keogan M, Exley A, et al.

28. Clinical effectiveness and cost – consequences of selective serotonin reuptake inhibitors in the treatment of sex offenders.

    By Adi Y, Ashcroft D, Browne K, Beech A, Fry-Smith A, Hyde C.

29. Treatment of established osteoporosis: a systematic review and cost–utility analysis.

    By Kanis JA, Brazier JE, Stevenson M, Calvert NW, Lloyd Jones M.

30. Which anaesthetic agents are cost-effective in day surgery? Literature review, national survey of practice and randomised controlled trial.

    By Elliott RA, Payne K, Moore JK, Davies LM, Harper NJN, St Leger AS, et al.

31. Screening for hepatitis C among injecting drug users and in genitourinary medicine clinics: systematic reviews of effectiveness, modelling study and national survey of current practice.

    By Stein K, Dalziel K, Walker A, McIntyre L, Jenkins B, Horne J, et al.

32. The measurement of satisfaction with healthcare: implications for practice from a systematic review of the literature.

    By Crow R, Gage H, Hampson S, Hart J, Kimber A, Storey L, et al.

33. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review.

    By Garside R, Round A, Dalziel K, Stein K, Royle R.

34. A comparative study of hypertonic saline, daily and alternate-day rhDNase in children with cystic fibrosis.

    By Suri R, Wallis C, Bush A, Thompson S, Normand C, Flather M, et al.

35. A systematic review of the costs and effectiveness of different models of paediatric home care.

    By Parker G, Bhakta P, Lovett CA, Paisley S, Olsen R, Turner D, et al.

1. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study.

   By Egger M, Jüni P, Bartlett C, Holenstein F, Sterne J.

2. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of home versus hospital or satellite unit haemodialysis for people with end-stage renal failure.

   By Mowatt G, Vale L, Perez J, Wyness L, Fraser C, MacLeod A, et al.

3. Systematic review and economic evaluation of the effectiveness of infliximab for the treatment of Crohn’s disease.

   By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

4. A review of the clinical effectiveness and cost-effectiveness of routine anti-D prophylaxis for pregnant women who are rhesus negative.

   By Chilcott J, Lloyd Jones M, Wight J, Forman K, Wray J, Beverley C, et al.

5. Systematic review and evaluation of the use of tumour markers in paediatric oncology: Ewing’s sarcoma and neuroblastoma.

   By Riley RD, Burchill SA, Abrams KR, Heney D, Lambert PC, Jones DR, et al.

6. The cost-effectiveness of screening for Helicobacter pylori to reduce mortality and morbidity from gastric cancer and peptic ulcer disease: a discrete-event simulation model.

   By Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Bhandari P, et al.

7. The clinical effectiveness and cost-effectiveness of routine dental checks: a systematic review and economic evaluation.

   By Davenport C, Elley K, Salas C, Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

8. A multicentre randomised controlled trial assessing the costs and benefits of using structured information and analysis of women’s preferences in the management of menorrhagia.

   By Kennedy ADM, Sculpher MJ, Coulter A, Dwyer N, Rees M, Horsley S, et al.

9. Clinical effectiveness and cost–utility of photodynamic therapy for wet age-related macular degeneration: a systematic review and economic evaluation.

   By Meads C, Salas C, Roberts T, Moore D, Fry-Smith A, Hyde C.

10. Evaluation of molecular tests for prenatal diagnosis of chromosome abnormalities.

    By Grimshaw GM, Szczepura A, Hultén M, MacDonald F, Nevin NC, Sutton F, et al.

11. First and second trimester antenatal screening for Down’s syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS).

    By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L, Mackinson AM.

12. The effectiveness and cost-effectiveness of ultrasound locating devices for central venous access: a systematic review and economic evaluation.

    By Calvert N, Hind D, McWilliams RG, Thomas SM, Beverley C, Davidson A.

13. A systematic review of atypical antipsychotics in schizophrenia.

    By Bagnall A-M, Jones L, Lewis R, Ginnelly L, Glanville J, Torgerson D, et al.

14. Prostate Testing for Cancer and Treatment (ProtecT) feasibility study.

    By Donovan J, Hamdy F, Neal D, Peters T, Oliver S, Brindle L, et al.

15. Early thrombolysis for the treatment of acute myocardial infarction: a systematic review and economic evaluation.

    By Boland A, Dundar Y, Bagust A, Haycox A, Hill R, Mujica Mota R, et al.

16. Screening for fragile X syndrome: a literature review and modelling.

    By Song FJ, Barton P, Sleightholme V, Yao GL, Fry-Smith A.

17. Systematic review of endoscopic sinus surgery for nasal polyps.

    By Dalziel K, Stein K, Round A, Garside R, Royle P.

18. Towards efficient guidelines: how to monitor guideline use in primary care.

    By Hutchinson A, McIntosh A, Cox S, Gilbert C.

19. Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

    By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

20. Prioritisation of health technology assessment. The PATHS model: methods and case studies.

    By Townsend J, Buxton M, Harper G.

21. Systematic review of the clinical effectiveness and cost-effectiveness of tension-free vaginal tape for treatment of urinary stress incontinence.

    By Cody J, Wyness L, Wallace S, Glazener C, Kilonzo M, Stearns S, et al.

22. The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

    By Loveman E, Cave C, Green C, Royle P, Dunn N, Waugh N.

23. The role of modelling in prioritising and planning clinical trials.

    By Chilcott J, Brennan A, Booth A, Karnon J, Tappenden P.

24. Cost–benefit evaluation of routine influenza immunisation in people 65–74 years of age.

    By Allsup S, Gosney M, Haycox A, Regan M.

25. The clinical and cost-effectiveness of pulsatile machine perfusion versus cold storage of kidneys for transplantation retrieved from heart-beating and non-heart-beating donors.

    By Wight J, Chilcott J, Holmes M, Brewer N.

26. Can randomised trials rely on existing electronic data? A feasibility study to explore the value of routine data in health technology assessment.

    By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

27. Evaluating non-randomised intervention studies.

    By Deeks JJ, Dinnes J, D’Amico R, Sowden AJ, Sakarovitch C, Song F, et al.

28. A randomised controlled trial to assess the impact of a package comprising a patient-orientated, evidence-based self- help guidebook and patient-centred consultations on disease management and satisfaction in inflammatory bowel disease.

    By Kennedy A, Nelson E, Reeves D, Richardson G, Roberts C, Robinson A, et al.

29. The effectiveness of diagnostic tests for the assessment of shoulder pain due to soft tissue disorders: a systematic review.

    By Dinnes J, Loveman E, McIntyre L, Waugh N.

30. The value of digital imaging in diabetic retinopathy.

    By Sharp PF, Olson J, Strachan F, Hipwell J, Ludbrook A, O’Donnell M, et al.

31. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy.

    By Law M, Wald N, Morris J.

32. Clinical and cost-effectiveness of capecitabine and tegafur with uracil for the treatment of metastatic colorectal cancer: systematic review and economic evaluation.

    By Ward S, Kaltenthaler E, Cowan J, Brewer N.

33. Clinical and cost-effectiveness of new and emerging technologies for early localised prostate cancer: a systematic review.

    By Hummel S, Paisley S, Morgan A, Currie E, Brewer N.

34. Literature searching for clinical and cost-effectiveness studies used in health technology assessment reports carried out for the National Institute for Clinical Excellence appraisal system.

    By Royle P, Waugh N.

35. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B.

    By Turner D, Wailoo A, Nicholson K, Cooper N, Sutton A, Abrams K.

36. A randomised controlled trial to evaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients by nurses.

    By Boland A, Haycox A, Bagust A, Fitzsimmons L.

37. Redesigning postnatal care: a randomised controlled trial of protocol-based midwifery-led care focused on individual women’s physical and psychological health needs.

    By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ, Knowles H, et al.

38. Estimating implied rates of discount in healthcare decision-making.

    By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

39. Systematic review of isolation policies in the hospital management of methicillin-resistant Staphylococcus aureus: a review of the literature with epidemiological and economic modelling.

    By Cooper BS, Stone SP, Kibbler CC, Cookson BD, Roberts JA, Medley GF, et al.

40. Treatments for spasticity and pain in multiple sclerosis: a systematic review.

    By Beard S, Hunn A, Wight J.

41. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.

    By Moher D, Pham B, Lawson ML, Klassen TP.

42. The impact of screening on future health-promoting behaviours and health beliefs: a systematic review.

    By Bankhead CR, Brett J, Bukach C, Webster P, Stewart-Brown S, Munafo M, et al.

1. What is the best imaging strategy for acute stroke?

   By Wardlaw JM, Keir SL, Seymour J, Lewis S, Sandercock PAG, Dennis MS, et al.

2. Systematic review and modelling of the investigation of acute and chronic chest pain presenting in primary care.

   By Mant J, McManus RJ, Oakes RAL, Delaney BC, Barton PM, Deeks JJ, et al.

3. The effectiveness and cost-effectiveness of microwave and thermal balloon endometrial ablation for heavy menstrual bleeding: a systematic review and economic modelling.

   By Garside R, Stein K, Wyatt K, Round A, Price A.

4. A systematic review of the role of bisphosphonates in metastatic disease.

   By Ross JR, Saunders Y, Edmonds PM, Patel S, Wonderling D, Normand C, et al.

5. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda^®) for locally advanced and/or metastatic breast cancer.

   By Jones L, Hawkins N, Westwood M, Wright K, Richardson G, Riemsma R.

6. Effectiveness and efficiency of guideline dissemination and implementation strategies.

   By Grimshaw JM, Thomas RE, MacLennan G, Fraser C, Ramsay CR, Vale L, et al.

7. Clinical effectiveness and costs of the Sugarbaker procedure for the treatment of pseudomyxoma peritonei.

   By Bryant J, Clegg AJ, Sidhu MK, Brodin H, Royle P, Davidson P.

8. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use.

   By Morgan K, Dixon S, Mathers N, Thompson J, Tomeny M.

9. Improving the evaluation of therapeutic interventions in multiple sclerosis: development of a patient-based measure of outcome.

   By Hobart JC, Riazi A, Lamping DL, Fitzpatrick R, Thompson AJ.

10. A systematic review and economic evaluation of magnetic resonance cholangiopancreatography compared with diagnostic endoscopic retrograde cholangiopancreatography.

    By Kaltenthaler E, Bravo Vergel Y, Chilcott J, Thomas S, Blakeborough T, Walters SJ, et al.

11. The use of modelling to evaluate new drugs for patients with a chronic condition: the case of antibodies against tumour necrosis factor in rheumatoid arthritis.

    By Barton P, Jobanputra P, Wilson J, Bryan S, Burls A.

12. Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

    By Pandor A, Eastham J, Beverley C, Chilcott J, Paisley S.

13. Clinical effectiveness and cost-effectiveness of pioglitazone and rosiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

    By Czoski-Murray C, Warren E, Chilcott J, Beverley C, Psyllaki MA, Cowan J.

14. Routine examination of the newborn: the EMREN study. Evaluation of an extension of the midwife role including a randomised controlled trial of appropriately trained midwives and paediatric senior house officers.

    By Townsend J, Wolke D, Hayes J, Davé S, Rogers C, Bloomfield L, et al.

15. Involving consumers in research and development agenda setting for the NHS: developing an evidence-based approach.

    By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

16. A multi-centre randomised controlled trial of minimally invasive direct coronary bypass grafting versus percutaneous transluminal coronary angioplasty with stenting for proximal stenosis of the left anterior descending coronary artery.

    By Reeves BC, Angelini GD, Bryan AJ, Taylor FC, Cripps T, Spyt TJ, et al.

17. Does early magnetic resonance imaging influence management or improve outcome in patients referred to secondary care with low back pain? A pragmatic randomised controlled trial.

    By Gilbert FJ, Grant AM, Gillan MGC, Vale L, Scott NW, Campbell MK, et al.

18. The clinical and cost-effectiveness of anakinra for the treatment of rheumatoid arthritis in adults: a systematic review and economic analysis.

    By Clark W, Jobanputra P, Barton P, Burls A.

19. A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

    By Bridle C, Palmer S, Bagnall A-M, Darba J, Duffy S, Sculpher M, et al.

20. Liquid-based cytology in cervical screening: an updated rapid and systematic review and economic analysis.

    By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

21. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

    By Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC, et al.

22. Autoantibody testing in children with newly diagnosed type 1 diabetes mellitus.

    By Dretzke J, Cummins C, Sandercock J, Fry-Smith A, Barrett T, Burls A.

23. Clinical effectiveness and cost-effectiveness of prehospital intravenous fluids in trauma patients.

    By Dretzke J, Sandercock J, Bayliss S, Burls A.

24. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation.

    By Dündar Y, Boland A, Strobl J, Dodd S, Haycox A, Bagust A, et al.

25. Development and validation of methods for assessing the quality of diagnostic accuracy studies.

    By Whiting P, Rutjes AWS, Dinnes J, Reitsma JB, Bossuyt PMM, Kleijnen J.

26. EVALUATE hysterectomy trial: a multicentre randomised trial comparing abdominal, vaginal and laparoscopic methods of hysterectomy.

    By Garry R, Fountain J, Brown J, Manca A, Mason S, Sculpher M, et al.

27. Methods for expected value of information analysis in complex health economic models: developments on the health economics of interferon-β and glatiramer acetate for multiple sclerosis.

    By Tappenden P, Chilcott JB, Eggington S, Oakley J, McCabe C.

28. Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis.

    By Dalziel K, Round A, Stein K, Garside R, Price A.

29. VenUS I: a randomised controlled trial of two types of bandage for treating venous leg ulcers.

    By Iglesias C, Nelson EA, Cullum NA, Torgerson DJ, on behalf of the VenUS Team.

30. Systematic review of the effectiveness and cost-effectiveness, and economic evaluation, of myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction.

    By Mowatt G, Vale L, Brazzelli M, Hernandez R, Murray A, Scott N, et al.

31. A pilot study on the use of decision theory and value of information analysis as part of the NHS Health Technology Assessment programme.

    By Claxton K, Ginnelly L, Sculpher M, Philips Z, Palmer S.

32. The Social Support and Family Health Study: a randomised controlled trial and economic evaluation of two alternative forms of postnatal support for mothers living in disadvantaged inner-city areas.

    By Wiggins M, Oakley A, Roberts I, Turner H, Rajan L, Austerberry H, et al.

33. Psychosocial aspects of genetic screening of pregnant women and newborns: a systematic review.

    By Green JM, Hewison J, Bekker HL, Bryant LD, Cuckle HS.

34. Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

    By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

35. Coronary artery stents: a rapid systematic review and economic evaluation.

    By Hill R, Bagust A, Bakhai A, Dickson R, Dündar Y, Haycox A, et al.

36. Review of guidelines for good practice in decision-analytic modelling in health technology assessment.

    By Philips Z, Ginnelly L, Sculpher M, Claxton K, Golder S, Riemsma R, et al.

37. Rituximab (MabThera^®) for aggressive non-Hodgkin’s lymphoma: systematic review and economic evaluation.

    By Knight C, Hind D, Brewer N, Abbott V.

38. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation.

    By Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, et al.

39. Pegylated interferon α-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Brodin H, Cave C, Waugh N, Price A, Gabbay J.

40. Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment- elevation acute coronary syndromes: a systematic review and economic evaluation.

    By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

41. Provision, uptake and cost of cardiac rehabilitation programmes: improving services to under-represented groups.

    By Beswick AD, Rees K, Griebsch I, Taylor FC, Burke M, West RR, et al.

42. Involving South Asian patients in clinical trials.

    By Hussain-Gambles M, Leese B, Atkin K, Brown J, Mason S, Tovey P.

43. Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes.

    By Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N.

44. Identification and assessment of ongoing trials in health technology assessment reviews.

    By Song FJ, Fry-Smith A, Davenport C, Bayliss S, Adi Y, Wilson JS, et al.

45. Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine

    By Warren E, Weatherley-Jones E, Chilcott J, Beverley C.

46. Supplementation of a home-based exercise programme with a class-based programme for people with osteoarthritis of the knees: a randomised controlled trial and health economic analysis.

    By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N, Roberts CR, et al.

47. Clinical and cost-effectiveness of once-daily versus more frequent use of same potency topical corticosteroids for atopic eczema: a systematic review and economic evaluation.

    By Green C, Colquitt JL, Kirby J, Davidson P, Payne E.

48. Acupuncture of chronic headache disorders in primary care: randomised controlled trial and economic analysis.

    By Vickers AJ, Rees RW, Zollman CE, McCarney R, Smith CM, Ellis N, et al.

49. Generalisability in economic evaluation studies in healthcare: a review and case studies.

    By Sculpher MJ, Pang FS, Manca A, Drummond MF, Golder S, Urdahl H, et al.

50. Virtual outreach: a randomised controlled trial and economic evaluation of joint teleconferenced medical consultations.

    By Wallace P, Barber J, Clayton W, Currell R, Fleming K, Garner P, et al.

1. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne.

   By Ozolins M, Eady EA, Avery A, Cunliffe WJ, O’Neill C, Simpson NB, et al.

2. Do the findings of case series studies vary significantly according to methodological characteristics?

   By Dalziel K, Round A, Stein K, Garside R, Castelnuovo E, Payne L.

3. Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

   By Wilson BJ, Torrance N, Mollison J, Wordsworth S, Gray JR, Haites NE, et al.

4. Randomised evaluation of alternative electrosurgical modalities to treat bladder outflow obstruction in men with benign prostatic hyperplasia.

   By Fowler C, McAllister W, Plail R, Karim O, Yang Q.

5. A pragmatic randomised controlled trial of the cost-effectiveness of palliative therapies for patients with inoperable oesophageal cancer.

   By Shenfine J, McNamee P, Steen N, Bond J, Griffin SM.

6. Impact of computer-aided detection prompts on the sensitivity and specificity of screening mammography.

   By Taylor P, Champness J, Given- Wilson R, Johnston K, Potts H.

7. Issues in data monitoring and interim analysis of trials.

   By Grant AM, Altman DG, Babiker AB, Campbell MK, Clemens FJ, Darbyshire JH, et al.

8. Lay public’s understanding of equipoise and randomisation in randomised controlled trials.

   By Robinson EJ, Kerr CEP, Stevens AJ, Lilford RJ, Braunholtz DA, Edwards SJ, et al.

9. Clinical and cost-effectiveness of electroconvulsive therapy for depressive illness, schizophrenia, catatonia and mania: systematic reviews and economic modelling studies.

   By Greenhalgh J, Knight C, Hind D, Beverley C, Walters S.

10. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology.

    By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

11. Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris^®) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

    By Green C, Dinnes J, Takeda A, Shepherd J, Hartwell D, Cave C, et al.

12. A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.

    By Dinnes J, Deeks J, Kirby J, Roderick P.

13. Cervical screening programmes: can automation help? Evidence from systematic reviews, an economic analysis and a simulation modelling exercise applied to the UK.

    By Willis BH, Barton P, Pearmain P, Bryan S, Hyde C.

14. Laparoscopic surgery for inguinal hernia repair: systematic review of effectiveness and economic evaluation.

    By McCormack K, Wake B, Perez J, Fraser C, Cook J, McIntosh E, et al.

15. Clinical effectiveness, tolerability and cost-effectiveness of newer drugs for epilepsy in adults: a systematic review and economic evaluation.

    By Wilby J, Kainth A, Hawkins N, Epstein D, McIntosh H, McDaid C, et al.

16. A randomised controlled trial to compare the cost-effectiveness of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine.

    By Peveler R, Kendrick T, Buxton M, Longworth L, Baldwin D, Moore M, et al.

17. Clinical effectiveness and cost-effectiveness of immediate angioplasty for acute myocardial infarction: systematic review and economic evaluation.

    By Hartwell D, Colquitt J, Loveman E, Clegg AJ, Brodin H, Waugh N, et al.

18. A randomised controlled comparison of alternative strategies in stroke care.

    By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

19. The investigation and analysis of critical incidents and adverse events in healthcare.

    By Woloshynowych M, Rogers S, Taylor-Adams S, Vincent C.

20. Potential use of routine databases in health technology assessment.

    By Raftery J, Roderick P, Stevens A.

21. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study.

    By Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, et al.

22. A systematic review and economic evaluation of alendronate, etidronate, risedronate, raloxifene and teriparatide for the prevention and treatment of postmenopausal osteoporosis.

    By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

23. A systematic review to examine the impact of psycho-educational interventions on health outcomes and costs in adults and children with difficult asthma.

    By Smith JR, Mugford M, Holland R, Candy B, Noble MJ, Harrison BDW, et al.

24. An evaluation of the costs, effectiveness and quality of renal replacement therapy provision in renal satellite units in England and Wales.

    By Roderick P, Nicholson T, Armitage A, Mehta R, Mullee M, Gerard K, et al.

25. Imatinib for the treatment of patients with unresectable and/or metastatic gastrointestinal stromal tumours: systematic review and economic evaluation.

    By Wilson J, Connock M, Song F, Yao G, Fry-Smith A, Raftery J, et al.

26. Indirect comparisons of competing interventions.

    By Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D’Amico R, et al.

27. Cost-effectiveness of alternative strategies for the initial medical management of non-ST elevation acute coronary syndrome: systematic review and decision-analytical modelling.

    By Robinson M, Palmer S, Sculpher M, Philips Z, Ginnelly L, Bowens A, et al.

28. Outcomes of electrically stimulated gracilis neosphincter surgery.

    By Tillin T, Chambers M, Feldman R.

29. The effectiveness and cost-effectiveness of pimecrolimus and tacrolimus for atopic eczema: a systematic review and economic evaluation.

    By Garside R, Stein K, Castelnuovo E, Pitt M, Ashcroft D, Dimmock P, et al.

30. Systematic review on urine albumin testing for early detection of diabetic complications.

    By Newman DJ, Mattock MB, Dawnay ABS, Kerry S, McGuire A, Yaqoob M, et al.

31. Randomised controlled trial of the cost-effectiveness of water-based therapy for lower limb osteoarthritis.

    By Cochrane T, Davey RC, Matthes Edwards SM.

32. Longer term clinical and economic benefits of offering acupuncture care to patients with chronic low back pain.

    By Thomas KJ, MacPherson H, Ratcliffe J, Thorpe L, Brazier J, Campbell M, et al.

33. Cost-effectiveness and safety of epidural steroids in the management of sciatica.

    By Price C, Arden N, Coglan L, Rogers P.

34. The British Rheumatoid Outcome Study Group (BROSG) randomised controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis.

    By Symmons D, Tricker K, Roberts C, Davies L, Dawes P, Scott DL.

35. Conceptual framework and systematic review of the effects of participants’ and professionals’ preferences in randomised controlled trials.

    By King M, Nazareth I, Lampe F, Bower P, Chandler M, Morou M, et al.

36. The clinical and cost-effectiveness of implantable cardioverter defibrillators: a systematic review.

    By Bryant J, Brodin H, Loveman E, Payne E, Clegg A.

37. A trial of problem-solving by community mental health nurses for anxiety, depression and life difficulties among general practice patients. The CPN-GP study.

    By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J, Pickering R, et al.

38. The causes and effects of socio-demographic exclusions from clinical trials.

    By Bartlett C, Doyal L, Ebrahim S, Davey P, Bachmann M, Egger M, et al.

39. Is hydrotherapy cost-effective? A randomised controlled trial of combined hydrotherapy programmes compared with physiotherapy land techniques in children with juvenile idiopathic arthritis.

    By Epps H, Ginnelly L, Utley M, Southwood T, Gallivan S, Sculpher M, et al.

40. A randomised controlled trial and cost-effectiveness study of systematic screening (targeted and total population screening) versus routine practice for the detection of atrial fibrillation in people aged 65 and over. The SAFE study.

    By Hobbs FDR, Fitzmaurice DA, Mant J, Murray E, Jowett S, Bryan S, et al.

41. Displaced intracapsular hip fractures in fit, older people: a randomised comparison of reduction and fixation, bipolar hemiarthroplasty and total hip arthroplasty.

    By Keating JF, Grant A, Masson M, Scott NW, Forbes JF.

42. Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

    By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR, Major KA, et al.

43. The effectiveness and cost-effectiveness of dual-chamber pacemakers compared with single-chamber pacemakers for bradycardia due to atrioventricular block or sick sinus syndrome: systematic review and economic evaluation.

    By Castelnuovo E, Stein K, Pitt M, Garside R, Payne E.

44. Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

    By Knowles R, Griebsch I, Dezateux C, Brown J, Bull C, Wren C.

45. The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.

    By Clegg AJ, Scott DA, Loveman E, Colquitt J, Hutchinson J, Royle P, et al.

46. The effectiveness of the Heidelberg Retina Tomograph and laser diagnostic glaucoma scanning system (GDx) in detecting and monitoring glaucoma.

    By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

47. Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints: systematic review and economic evaluation.

    By Clar C, Cummins E, McIntyre L, Thomas S, Lamb J, Bain L, et al.

48. Systematic review of effectiveness of different treatments for childhood retinoblastoma.

    By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K, Riemsma R.

49. Towards evidence-based guidelines for the prevention of venous thromboembolism: systematic reviews of mechanical methods, oral anticoagulation, dextran and regional anaesthesia as thromboprophylaxis.

    By Roderick P, Ferris G, Wilson K, Halls H, Jackson D, Collins R, et al.

50. The effectiveness and cost-effectiveness of parent training/education programmes for the treatment of conduct disorder, including oppositional defiant disorder, in children.

    By Dretzke J, Frew E, Davenport C, Barlow J, Stewart-Brown S, Sandercock J, et al.

1. The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer’s disease.

   By Loveman E, Green C, Kirby J, Takeda A, Picot J, Payne E, et al.

2. FOOD: a multicentre randomised trial evaluating feeding policies in patients admitted to hospital with a recent stroke.

   By Dennis M, Lewis S, Cranswick G, Forbes J.

3. The clinical effectiveness and cost-effectiveness of computed tomography screening for lung cancer: systematic reviews.

   By Black C, Bagust A, Boland A, Walker S, McLeod C, De Verteuil R, et al.

4. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery.

   By Whiting P, Gupta R, Burch J, Mujica Mota RE, Wright K, Marson A, et al.

5. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies.

   By Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR.

6. Systematic review and evaluation of methods of assessing urinary incontinence.

   By Martin JL, Williams KS, Abrams KR, Turner DA, Sutton AJ, Chapple C, et al.

7. The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

   By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

8. Surveillance of Barrett’s oesophagus: exploring the uncertainty through systematic review, expert workshop and economic modelling.

   By Garside R, Pitt M, Somerville M, Stein K, Price A, Gilbert N.

9. Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.

   By Main C, Bojke L, Griffin S, Norman G, Barbieri M, Mather L, et al.

10. Evaluation of molecular techniques in prediction and diagnosis of cytomegalovirus disease in immunocompromised patients.

    By Szczepura A, Westmoreland D, Vinogradova Y, Fox J, Clark M.

11. Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.

    By Wu O, Robertson L, Twaddle S, Lowe GDO, Clark P, Greaves M, et al.

12. A series of systematic reviews to inform a decision analysis for sampling and treating infected diabetic foot ulcers.

    By Nelson EA, O’Meara S, Craig D, Iglesias C, Golder S, Dalton J, et al.

13. Randomised clinical trial, observational study and assessment of cost-effectiveness of the treatment of varicose veins (REACTIV trial).

    By Michaels JA, Campbell WB, Brazier JE, MacIntyre JB, Palfreyman SJ, Ratcliffe J, et al.

14. The cost-effectiveness of screening for oral cancer in primary care.

    By Speight PM, Palmer S, Moles DR, Downer MC, Smith DH, Henriksson M, et al.

15. Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.

    By Goodacre S, Sampson F, Stevenson M, Wailoo A, Sutton A, Thomas S, et al.

16. Systematic review of the effectiveness and cost-effectiveness of HealOzone^® for the treatment of occlusal pit/fissure caries and root caries.

    By Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al.

17. Randomised controlled trials of conventional antipsychotic versus new atypical drugs, and new atypical drugs versus clozapine, in people with schizophrenia responding poorly to, or intolerant of, current drug treatment.

    By Lewis SW, Davies L, Jones PB, Barnes TRE, Murray RM, Kerwin R, et al.

18. Diagnostic tests and algorithms used in the investigation of haematuria: systematic reviews and economic evaluation.

    By Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, et al.

19. Cognitive behavioural therapy in addition to antispasmodic therapy for irritable bowel syndrome in primary care: randomised controlled trial.

    By Kennedy TM, Chalder T, McCrone P, Darnley S, Knapp M, Jones RH, et al.

20. A systematic review of the clinical effectiveness and cost-effectiveness of enzyme replacement therapies for Fabry’s disease and mucopolysaccharidosis type 1.

    By Connock M, Juarez-Garcia A, Frew E, Mans A, Dretzke J, Fry-Smith A, et al.

21. Health benefits of antiviral therapy for mild chronic hepatitis C: randomised controlled trial and economic evaluation.

    By Wright M, Grieve R, Roberts J, Main J, Thomas HC, on behalf of the UK Mild Hepatitis C Trial Investigators.

22. Pressure relieving support surfaces: a randomised evaluation.

    By Nixon J, Nelson EA, Cranny G, Iglesias CP, Hawkins K, Cullum NA, et al.

23. A systematic review and economic model of the effectiveness and cost-effectiveness of methylphenidate, dexamfetamine and atomoxetine for the treatment of attention deficit hyperactivity disorder in children and adolescents.

    By King S, Griffin S, Hodges Z, Weatherly H, Asseburg C, Richardson G, et al.

24. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review.

    By Connock M, Burls A, Frew E, Fry-Smith A, Juarez-Garcia A, McCabe C, et al.

25. Effectiveness and cost-effectiveness of salicylic acid and cryotherapy for cutaneous warts. An economic decision model.

    By Thomas KS, Keogh-Brown MR, Chalmers JR, Fordham RJ, Holland RC, Armstrong SJ, et al.

26. A systematic literature review of the effectiveness of non-pharmacological interventions to prevent wandering in dementia and evaluation of the ethical implications and acceptability of their use.

    By Robinson L, Hutchings D, Corner L, Beyer F, Dickinson H, Vanoli A, et al.

27. A review of the evidence on the effects and costs of implantable cardioverter defibrillator therapy in different patient groups, and modelling of cost-effectiveness and cost–utility for these groups in a UK context.

    By Buxton M, Caine N, Chase D, Connelly D, Grace A, Jackson C, et al.

28. Adefovir dipivoxil and pegylated interferon alfa-2a for the treatment of chronic hepatitis B: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Takeda A, Davidson P, Price A.

29. An evaluation of the clinical and cost-effectiveness of pulmonary artery catheters in patient management in intensive care: a systematic review and a randomised controlled trial.

    By Harvey S, Stevens K, Harrison D, Young D, Brampton W, McCabe C, et al.

30. Accurate, practical and cost-effective assessment of carotid stenosis in the UK.

    By Wardlaw JM, Chappell FM, Stevenson M, De Nigris E, Thomas S, Gillard J, et al.

31. Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.

    By Woolacott N, Bravo Vergel Y, Hawkins N, Kainth A, Khadjesari Z, Misso K, et al.

32. The cost-effectiveness of testing for hepatitis C in former injecting drug users.

    By Castelnuovo E, Thompson-Coon J, Pitt M, Cramp M, Siebert U, Price A, et al.

33. Computerised cognitive behaviour therapy for depression and anxiety update: a systematic review and economic evaluation.

    By Kaltenthaler E, Brazier J, De Nigris E, Tumur I, Ferriter M, Beverley C, et al.

34. Cost-effectiveness of using prognostic information to select women with breast cancer for adjuvant systemic therapy.

    By Williams C, Brunskill S, Altman D, Briggs A, Campbell H, Clarke M, et al.

35. Psychological therapies including dialectical behaviour therapy for borderline personality disorder: a systematic review and preliminary economic evaluation.

    By Brazier J, Tumur I, Holmes M, Ferriter M, Parry G, Dent-Brown K, et al.

36. Clinical effectiveness and cost-effectiveness of tests for the diagnosis and investigation of urinary tract infection in children: a systematic review and economic model.

    By Whiting P, Westwood M, Bojke L, Palmer S, Richardson G, Cooper J, et al.

37. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme.

    By O’Dowd H, Gladwell P, Rogers CA, Hollinghurst S, Gregory A.

38. A comparison of the cost-effectiveness of five strategies for the prevention of nonsteroidal anti-inflammatory drug-induced gastrointestinal toxicity: a systematic review with economic modelling.

    By Brown TJ, Hooper L, Elliott RA, Payne K, Webb R, Roberts C, et al.

39. The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease: systematic review.

    By Waugh N, Black C, Walker S, McIntyre L, Cummins E, Hillis G.

40. What are the clinical outcome and cost-effectiveness of endoscopy undertaken by nurses when compared with doctors? A Multi-Institution Nurse Endoscopy Trial (MINuET).

    By Williams J, Russell I, Durai D, Cheung W-Y, Farrin A, Bloor K, et al.

41. The clinical and cost-effectiveness of oxaliplatin and capecitabine for the adjuvant treatment of colon cancer: systematic review and economic evaluation.

    By Pandor A, Eggington S, Paisley S, Tappenden P, Sutcliffe P.

42. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness.

    By Chen Y-F, Jobanputra P, Barton P, Jowett S, Bryan S, Clark W, et al.

43. Telemedicine in dermatology: a randomised controlled trial.

    By Bowns IR, Collins K, Walters SJ, McDonagh AJG.

44. Cost-effectiveness of cell salvage and alternative methods of minimising perioperative allogeneic blood transfusion: a systematic review and economic model.

    By Davies L, Brown TJ, Haynes S, Payne K, Elliott RA, McCollum C.

45. Clinical effectiveness and cost-effectiveness of laparoscopic surgery for colorectal cancer: systematic reviews and economic evaluation.

    By Murray A, Lourenco T, de Verteuil R, Hernandez R, Fraser C, McKinley A, et al.

46. Etanercept and efalizumab for the treatment of psoriasis: a systematic review.

    By Woolacott N, Hawkins N, Mason A, Kainth A, Khadjesari Z, Bravo Vergel Y, et al.

47. Systematic reviews of clinical decision tools for acute abdominal pain.

    By Liu JLY, Wyatt JC, Deeks JJ, Clamp S, Keen J, Verde P, et al.

48. Evaluation of the ventricular assist device programme in the UK.

    By Sharples L, Buxton M, Caine N, Cafferty F, Demiris N, Dyer M, et al.

49. A systematic review and economic model of the clinical and cost-effectiveness of immunosuppressive therapy for renal transplantation in children.

    By Yao G, Albon E, Adi Y, Milford D, Bayliss S, Ready A, et al.

50. Amniocentesis results: investigation of anxiety. The ARIA trial.

    By Hewison J, Nixon J, Fountain J, Cocks K, Jones C, Mason G, et al.

1. Pemetrexed disodium for the treatment of malignant pleural mesothelioma: a systematic review and economic evaluation.

   By Dundar Y, Bagust A, Dickson R, Dodd S, Green J, Haycox A, et al.

2. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of docetaxel in combination with prednisone or prednisolone for the treatment of hormone-refractory metastatic prostate cancer.

   By Collins R, Fenwick E, Trowman R, Perard R, Norman G, Light K, et al.

3. A systematic review of rapid diagnostic tests for the detection of tuberculosis infection.

   By Dinnes J, Deeks J, Kunst H, Gibson A, Cummins E, Waugh N, et al.

4. The clinical effectiveness and cost-effectiveness of strontium ranelate for the prevention of osteoporotic fragility fractures in postmenopausal women.

   By Stevenson M, Davis S, Lloyd-Jones M, Beverley C.

5. A systematic review of quantitative and qualitative research on the role and effectiveness of written information available to patients about individual medicines.

   By Raynor DK, Blenkinsopp A, Knapp P, Grime J, Nicolson DJ, Pollock K, et al.

6. Oral naltrexone as a treatment for relapse prevention in formerly opioid-dependent drug users: a systematic review and economic evaluation.

   By Adi Y, Juarez-Garcia A, Wang D, Jowett S, Frew E, Day E, et al.

7. Glucocorticoid-induced osteoporosis: a systematic review and cost–utility analysis.

   By Kanis JA, Stevenson M, McCloskey EV, Davis S, Lloyd-Jones M.

8. Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

   By Low N, McCarthy A, Macleod J, Salisbury C, Campbell R, Roberts TE, et al.

9. Methadone and buprenorphine for the management of opioid dependence: a systematic review and economic evaluation.

   By Connock M, Juarez-Garcia A, Jowett S, Frew E, Liu Z, Taylor RJ, et al.

10. Exercise Evaluation Randomised Trial (EXERT): a randomised trial comparing GP referral for leisure centre-based exercise, community-based walking and advice only.

    By Isaacs AJ, Critchley JA, See Tai S, Buckingham K, Westley D, Harridge SDR, et al.

11. Interferon alfa (pegylated and non-pegylated) and ribavirin for the treatment of mild chronic hepatitis C: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Hartwell D, Davidson P, Price A, Waugh N.

12. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer.

    By Tappenden P, Jones R, Paisley S, Carroll C.

13. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer, especially that attributable to cancer treatment.

    By Wilson J, Yao GL, Raftery J, Bohlius J, Brunskill S, Sandercock J, et al.

14. A systematic review and economic evaluation of statins for the prevention of coronary events.

    By Ward S, Lloyd Jones M, Pandor A, Holmes M, Ara R, Ryan A, et al.

15. A systematic review of the effectiveness and cost-effectiveness of different models of community-based respite care for frail older people and their carers.

    By Mason A, Weatherly H, Spilsbury K, Arksey H, Golder S, Adamson J, et al.

16. Additional therapy for young children with spastic cerebral palsy: a randomised controlled trial.

    By Weindling AM, Cunningham CC, Glenn SM, Edwards RT, Reeves DJ.

17. Screening for type 2 diabetes: literature review and economic modelling.

    By Waugh N, Scotland G, McNamee P, Gillett M, Brennan A, Goyder E, et al.

18. The effectiveness and cost-effectiveness of cinacalcet for secondary hyperparathyroidism in end-stage renal disease patients on dialysis: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Mealing S, Roome C, Snaith A, et al.

19. The clinical effectiveness and cost-effectiveness of gemcitabine for metastatic breast cancer: a systematic review and economic evaluation.

    By Takeda AL, Jones J, Loveman E, Tan SC, Clegg AJ.

20. A systematic review of duplex ultrasound, magnetic resonance angiography and computed tomography angiography for the diagnosis and assessment of symptomatic, lower limb peripheral arterial disease.

    By Collins R, Cranny G, Burch J, Aguiar-Ibáñez R, Craig D, Wright K, et al.

21. The clinical effectiveness and cost-effectiveness of treatments for children with idiopathic steroid-resistant nephrotic syndrome: a systematic review.

    By Colquitt JL, Kirby J, Green C, Cooper K, Trompeter RS.

22. A systematic review of the routine monitoring of growth in children of primary school age to identify growth-related conditions.

    By Fayter D, Nixon J, Hartley S, Rithalia A, Butler G, Rudolf M, et al.

23. Systematic review of the effectiveness of preventing and treating Staphylococcus aureus carriage in reducing peritoneal catheter-related infections.

    By McCormack K, Rabindranath K, Kilonzo M, Vale L, Fraser C, McIntyre L, et al.

24. The clinical effectiveness and cost of repetitive transcranial magnetic stimulation versus electroconvulsive therapy in severe depression: a multicentre pragmatic randomised controlled trial and economic analysis.

    By McLoughlin DM, Mogg A, Eranti S, Pluck G, Purvis R, Edwards D, et al.

25. A randomised controlled trial and economic evaluation of direct versus indirect and individual versus group modes of speech and language therapy for children with primary language impairment.

    By Boyle J, McCartney E, Forbes J, O’Hare A.

26. Hormonal therapies for early breast cancer: systematic review and economic evaluation.

    By Hind D, Ward S, De Nigris E, Simpson E, Carroll C, Wyld L.

27. Cardioprotection against the toxic effects of anthracyclines given to children with cancer: a systematic review.

    By Bryant J, Picot J, Levitt G, Sullivan I, Baxter L, Clegg A.

28. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation.

    By McLeod C, Bagust A, Boland A, Dagenais P, Dickson R, Dundar Y, et al.

29. Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

    By Colbourn T, Asseburg C, Bojke L, Philips Z, Claxton K, Ades AE, et al.

30. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review.

    By Garrison KR, Donell S, Ryder J, Shemilt I, Mugford M, Harvey I, et al.

31. A randomised controlled trial of postoperative radiotherapy following breast-conserving surgery in a minimum-risk older population. The PRIME trial.

    By Prescott RJ, Kunkler IH, Williams LJ, King CC, Jack W, van der Pol M, et al.

32. Current practice, accuracy, effectiveness and cost-effectiveness of the school entry hearing screen.

    By Bamford J, Fortnum H, Bristow K, Smith J, Vamvakas G, Davies L, et al.

33. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation.

    By Black C, Cummins E, Royle P, Philip S, Waugh N.

34. Surveillance of cirrhosis for hepatocellular carcinoma: systematic review and economic analysis.

    By Thompson Coon J, Rogers G, Hewson P, Wright D, Anderson R, Cramp M, et al.

35. The Birmingham Rehabilitation Uptake Maximisation Study (BRUM). Homebased compared with hospital-based cardiac rehabilitation in a multi-ethnic population: cost-effectiveness and patient adherence.

    By Jolly K, Taylor R, Lip GYH, Greenfield S, Raftery J, Mant J, et al.

36. A systematic review of the clinical, public health and cost-effectiveness of rapid diagnostic tests for the detection and identification of bacterial intestinal pathogens in faeces and food.

    By Abubakar I, Irvine L, Aldus CF, Wyatt GM, Fordham R, Schelenz S, et al.

37. A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

    By Marson AG, Appleton R, Baker GA, Chadwick DW, Doughty J, Eaton B, et al.

38. Clinical effectiveness and cost-effectiveness of different models of managing long-term oral anti-coagulation therapy: a systematic review and economic modelling.

    By Connock M, Stevens C, Fry-Smith A, Jowett S, Fitzmaurice D, Moore D, et al.

39. A systematic review and economic model of the clinical effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder.

    By Soares-Weiser K, Bravo Vergel Y, Beynon S, Dunn G, Barbieri M, Duffy S, et al.

40. Taxanes for the adjuvant treatment of early breast cancer: systematic review and economic evaluation.

    By Ward S, Simpson E, Davis S, Hind D, Rees A, Wilkinson A.

41. The clinical effectiveness and cost-effectiveness of screening for open angle glaucoma: a systematic review and economic evaluation.

    By Burr JM, Mowatt G, Hernández R, Siddiqui MAR, Cook J, Lourenco T, et al.

42. Acceptability, benefit and costs of early screening for hearing disability: a study of potential screening tests and models.

    By Davis A, Smith P, Ferguson M, Stephens D, Gianopoulos I.

43. Contamination in trials of educational interventions.

    By Keogh-Brown MR, Bachmann MO, Shepstone L, Hewitt C, Howe A, Ramsay CR, et al.

44. Overview of the clinical effectiveness of positron emission tomography imaging in selected cancers.

    By Facey K, Bradbury I, Laking G, Payne E.

45. The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation.

    By Garside R, Pitt M, Anderson R, Rogers G, Dyer M, Mealing S, et al.

46. Drug-eluting stents: a systematic review and economic evaluation.

    By Hill RA, Boland A, Dickson R, Dündar Y, Haycox A, McLeod C, et al.

47. The clinical effectiveness and cost-effectiveness of cardiac resynchronisation (biventricular pacing) for heart failure: systematic review and economic model.

    By Fox M, Mealing S, Anderson R, Dean J, Stein K, Price A, et al.

48. Recruitment to randomised trials: strategies for trial enrolment and participation study. The STEPS study.

    By Campbell MK, Snowdon C, Francis D, Elbourne D, McDonald AM, Knight R, et al.

49. Cost-effectiveness of functional cardiac testing in the diagnosis and management of coronary artery disease: a randomised controlled trial. The CECaT trial.

    By Sharples L, Hughes V, Crean A, Dyer M, Buxton M, Goldsmith K, et al.

50. Evaluation of diagnostic tests when there is no gold standard. A review of methods.

    By Rutjes AWS, Reitsma JB, Coomarasamy A, Khan KS, Bossuyt PMM.

51. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding.

    By Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al.

52. A review and critique of modelling in prioritising and designing screening programmes.

    By Karnon J, Goyder E, Tappenden P, McPhie S, Towers I, Brazier J, et al.

53. An assessment of the impact of the NHS Health Technology Assessment Programme.

    By Hanney S, Buxton M, Green C, Coulson D, Raftery J.

1. A systematic review and economic model of switching from nonglycopeptide to glycopeptide antibiotic prophylaxis for surgery.

   By Cranny G, Elliott R, Weatherly H, Chambers D, Hawkins N, Myers L, et al.

2. ‘Cut down to quit’ with nicotine replacement therapies in smoking cessation: a systematic review of effectiveness and economic analysis.

   By Wang D, Connock M, Barton P, Fry-Smith A, Aveyard P, Moore D.

3. A systematic review of the effectiveness of strategies for reducing fracture risk in children with juvenile idiopathic arthritis with additional data on long-term risk of fracture and cost of disease management.

   By Thornton J, Ashcroft D, O’Neill T, Elliott R, Adams J, Roberts C, et al.

4. Does befriending by trained lay workers improve psychological well-being and quality of life for carers of people with dementia, and at what cost? A randomised controlled trial.

   By Charlesworth G, Shepstone L, Wilson E, Thalanany M, Mugford M, Poland F.

5. A multi-centre retrospective cohort study comparing the efficacy, safety and cost-effectiveness of hysterectomy and uterine artery embolisation for the treatment of symptomatic uterine fibroids. The HOPEFUL study.

   By Hirst A, Dutton S, Wu O, Briggs A, Edwards C, Waldenmaier L, et al.

6. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling.

   By Meads CA, Cnossen JS, Meher S, Juarez-Garcia A, ter Riet G, Duley L, et al.

7. The use of economic evaluations in NHS decision-making: a review and empirical investigation.

   By Williams I, McIver S, Moore D, Bryan S.

8. Stapled haemorrhoidectomy (haemorrhoidopexy) for the treatment of haemorrhoids: a systematic review and economic evaluation.

   By Burch J, Epstein D, Baba-Akbari A, Weatherly H, Fox D, Golder S, et al.

9. The clinical effectiveness of diabetes education models for Type 2 diabetes: a systematic review.

   By Loveman E, Frampton GK, Clegg AJ.

10. Payment to healthcare professionals for patient recruitment to trials: systematic review and qualitative study.

    By Raftery J, Bryant J, Powell J, Kerr C, Hawker S.

11. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation.

    By Chen Y-F, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al.

12. The clinical effectiveness and cost-effectiveness of central venous catheters treated with anti-infective agents in preventing bloodstream infections: a systematic review and economic evaluation.

    By Hockenhull JC, Dwan K, Boland A, Smith G, Bagust A, Dundar Y, et al.

13. Stepped treatment of older adults on laxatives. The STOOL trial.

    By Mihaylov S, Stark C, McColl E, Steen N, Vanoli A, Rubin G, et al.

14. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

    By Goodyer IM, Dubicka B, Wilkinson P, Kelvin R, Roberts C, Byford S, et al.

15. The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation.

    By Hind D, Tappenden P, Tumur I, Eggington E, Sutcliffe P, Ryan A.

16. Ranibizumab and pegaptanib for the treatment of age-related macular degeneration: a systematic review and economic evaluation.

    By Colquitt JL, Jones J, Tan SC, Takeda A, Clegg AJ, Price A.

17. Systematic review of the clinical effectiveness and cost-effectiveness of 64-slice or higher computed tomography angiography as an alternative to invasive coronary angiography in the investigation of coronary artery disease.

    By Mowatt G, Cummins E, Waugh N, Walker S, Cook J, Jia X, et al.

18. Structural neuroimaging in psychosis: a systematic review and economic evaluation.

    By Albon E, Tsourapas A, Frew E, Davenport C, Oyebode F, Bayliss S, et al.

19. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in adults and children aged 12 years and over.

    By Shepherd J, Rogers G, Anderson R, Main C, Thompson-Coon J, Hartwell D, et al.

20. Systematic review and economic analysis of the comparative effectiveness of different inhaled corticosteroids and their usage with long-acting beta₂ agonists for the treatment of chronic asthma in children under the age of 12 years.

    By Main C, Shepherd J, Anderson R, Rogers G, Thompson-Coon J, Liu Z, et al.

21. Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation.

    By Ara R, Tumur I, Pandor A, Duenas A, Williams R, Wilkinson A, et al.

22. Topical or oral ibuprofen for chronic knee pain in older people. The TOIB study.

    By Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross P, Harding G, et al.

23. A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

    By George S, Pockney P, Primrose J, Smith H, Little P, Kinley H, et al.

24. A review and critical appraisal of measures of therapist–patient interactions in mental health settings.

    By Cahill J, Barkham M, Hardy G, Gilbody S, Richards D, Bower P, et al.

25. The clinical effectiveness and cost-effectiveness of screening programmes for amblyopia and strabismus in children up to the age of 4–5 years: a systematic review and economic evaluation.

    By Carlton J, Karnon J, Czoski-Murray C, Smith KJ, Marr J.

26. A systematic review of the clinical effectiveness and cost-effectiveness and economic modelling of minimal incision total hip replacement approaches in the management of arthritic disease of the hip.

    By de Verteuil R, Imamura M, Zhu S, Glazener C, Fraser C, Munro N, et al.

27. A preliminary model-based assessment of the cost–utility of a screening programme for early age-related macular degeneration.

    By Karnon J, Czoski-Murray C, Smith K, Brand C, Chakravarthy U, Davis S, et al.

28. Intravenous magnesium sulphate and sotalol for prevention of atrial fibrillation after coronary artery bypass surgery: a systematic review and economic evaluation.

    By Shepherd J, Jones J, Frampton GK, Tanajewski L, Turner D, Price A.

29. Absorbent products for urinary/faecal incontinence: a comparative evaluation of key product categories.

    By Fader M, Cottenden A, Getliffe K, Gage H, Clarke-O’Neill S, Jamieson K, et al.

30. A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.

    By French B, Leathley M, Sutton C, McAdam J, Thomas L, Forster A, et al.

31. The effectiveness and cost-effectivness of minimal access surgery amongst people with gastro-oesophageal reflux disease – a UK collaborative study. The reflux trial.

    By Grant A, Wileman S, Ramsay C, Bojke L, Epstein D, Sculpher M, et al.

32. Time to full publication of studies of anti-cancer medicines for breast cancer and the potential for publication bias: a short systematic review.

    By Takeda A, Loveman E, Harris P, Hartwell D, Welch K.

33. Performance of screening tests for child physical abuse in accident and emergency departments.

    By Woodman J, Pitt M, Wentz R, Taylor B, Hodes D, Gilbert RE.

34. Curative catheter ablation in atrial fibrillation and typical atrial flutter: systematic review and economic evaluation.

    By Rodgers M, McKenna C, Palmer S, Chambers D, Van Hout S, Golder S, et al.

35. Systematic review and economic modelling of effectiveness and cost utility of surgical treatments for men with benign prostatic enlargement.

    By Lourenco T, Armstrong N, N’Dow J, Nabi G, Deverill M, Pickard R, et al.

36. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

    By Wang D, Cummins C, Bayliss S, Sandercock J, Burls A.

1. Deferasirox for the treatment of iron overload associated with regular blood transfusions (transfusional haemosiderosis) in patients suffering with chronic anaemia: a systematic review and economic evaluation.

   By McLeod C, Fleeman N, Kirkham J, Bagust A, Boland A, Chu P, et al.

2. Thrombophilia testing in people with venous thromboembolism: systematic review and cost-effectiveness analysis.

   By Simpson EL, Stevenson MD, Rawdin A, Papaioannou D.

3. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs.

   By Main C, Liu Z, Welch K, Weiner G, Quentin Jones S, Stein K.

4. Continuous positive airway pressure devices for the treatment of obstructive sleep apnoea–hypopnoea syndrome: a systematic review and economic analysis.

   By McDaid C, Griffin S, Weatherly H, Durée K, van der Burgt M, van Hout S, Akers J, et al.

5. Use of classical and novel biomarkers as prognostic risk factors for localised prostate cancer: a systematic review.

   By Sutcliffe P, Hummel S, Simpson E, Young T, Rees A, Wilkinson A, et al.

6. The harmful health effects of recreational ecstasy: a systematic review of observational evidence.

   By Rogers G, Elston J, Garside R, Roome C, Taylor R, Younger P, et al.

7. Systematic review of the clinical effectiveness and cost-effectiveness of oesophageal Doppler monitoring in critically ill and high-risk surgical patients.

   By Mowatt G, Houston G, Hernández R, de Verteuil R, Fraser C, Cuthbertson B, et al.

8. The use of surrogate outcomes in model-based cost-effectiveness analyses: a survey of UK Health Technology Assessment reports.

   By Taylor RS, Elston J.

9. Controlling Hypertension and Hypotension Immediately Post Stroke (CHHIPS) – a randomised controlled trial.

   By Potter J, Mistri A, Brodie F, Chernova J, Wilson E, Jagger C, et al.

10. Routine antenatal anti-D prophylaxis for RhD-negative women: a systematic review and economic evaluation.

    By Pilgrim H, Lloyd-Jones M, Rees A.

11. Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

    By Tappenden P, Jackson R, Cooper K, Rees A, Simpson E, Read R, et al.

12. Improving the evaluation of therapeutic interventions in multiple sclerosis: the role of new psychometric methods.

    By Hobart J, Cano S.

13. Treatment of severe ankle sprain: a pragmatic randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of three types of mechanical ankle support with tubular bandage. The CAST trial.

    By Cooke MW, Marsh JL, Clark M, Nakash R, Jarvis RM, Hutton JL, et al. , on behalf of the CAST trial group.

14. Non-occupational postexposure prophylaxis for HIV: a systematic review.

    By Bryant J, Baxter L, Hird S.

15. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial.

    By Farmer AJ, Wade AN, French DP, Simon J, Yudkin P, Gray A, et al.

16. How far does screening women for domestic (partner) violence in different health-care settings meet criteria for a screening programme? Systematic reviews of nine UK National Screening Committee criteria.

    By Feder G, Ramsay J, Dunne D, Rose M, Arsene C, Norman R, et al.

17. Spinal cord stimulation for chronic pain of neuropathic or ischaemic origin: systematic review and economic evaluation.

    By Simpson EL, Duenas A, Holmes MW, Papaioannou D, Chilcott J.

18. The role of magnetic resonance imaging in the identification of suspected acoustic neuroma: a systematic review of clinical and cost-effectiveness and natural history.

    By Fortnum H, O’Neill C, Taylor R, Lenthall R, Nikolopoulos T, Lightfoot G, et al.

19. Dipsticks and diagnostic algorithms in urinary tract infection: development and validation, randomised trial, economic analysis, observational cohort and qualitative study.

    By Little P, Turner S, Rumsby K, Warner G, Moore M, Lowes JA, et al.

20. Systematic review of respite care in the frail elderly.

    By Shaw C, McNamara R, Abrams K, Cannings-John R, Hood K, Longo M, et al.

21. Neuroleptics in the treatment of aggressive challenging behaviour for people with intellectual disabilities: a randomised controlled trial (NACHBID).

    By Tyrer P, Oliver-Africano P, Romeo R, Knapp M, Dickens S, Bouras N, et al.

22. Randomised controlled trial to determine the clinical effectiveness and cost-effectiveness of selective serotonin reuptake inhibitors plus supportive care, versus supportive care alone, for mild to moderate depression with somatic symptoms in primary care: the THREAD (THREshold for AntiDepressant response) study.

    By Kendrick T, Chatwin J, Dowrick C, Tylee A, Morriss R, Peveler R, et al.

23. Diagnostic strategies using DNA testing for hereditary haemochromatosis in at-risk populations: a systematic review and economic evaluation.

    By Bryant J, Cooper K, Picot J, Clegg A, Roderick P, Rosenberg W, et al.

24. Enhanced external counterpulsation for the treatment of stable angina and heart failure: a systematic review and economic analysis.

    By McKenna C, McDaid C, Suekarran S, Hawkins N, Claxton K, Light K, et al.

25. Development of a decision support tool for primary care management of patients with abnormal liver function tests without clinically apparent liver disease: a record-linkage population cohort study and decision analysis (ALFIE).

    By Donnan PT, McLernon D, Dillon JF, Ryder S, Roderick P, Sullivan F, et al.

26. A systematic review of presumed consent systems for deceased organ donation.

    By Rithalia A, McDaid C, Suekarran S, Norman G, Myers L, Sowden A.

27. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial.

    By Hay AD, Redmond NM, Costelloe C, Montgomery AA, Fletcher M, Hollinghurst S, et al.

28. A randomised controlled trial to compare minimally invasive glucose monitoring devices with conventional monitoring in the management of insulin-treated diabetes mellitus (MITRE).

    By Newman SP, Cooke D, Casbard A, Walker S, Meredith S, Nunn A, et al.

29. Sensitivity analysis in economic evaluation: an audit of NICE current practice and a review of its use and value in decision-making.

    By Andronis L, Barton P, Bryan S.

30. Trastuzumab for the treatment of primary breast cancer in HER2-positive women: a single technology appraisal.

    By Ward S, Pilgrim H, Hind D.

31. Docetaxel for the adjuvant treatment of early node-positive breast cancer: a single technology appraisal.

    By Chilcott J, Lloyd Jones M, Wilkinson A.

32. The use of paclitaxel in the management of early stage breast cancer.

    By Griffin S, Dunn G, Palmer S, Macfarlane K, Brent S, Dyker A, et al.

33. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin’s lymphoma.

    By Dundar Y, Bagust A, Hounsome J, McLeod C, Boland A, Davis H, et al.

34. Bortezomib for the treatment of multiple myeloma patients.

    By Green C, Bryant J, Takeda A, Cooper K, Clegg A, Smith A, et al.

35. Fludarabine phosphate for the firstline treatment of chronic lymphocytic leukaemia.

    By Walker S, Palmer S, Erhorn S, Brent S, Dyker A, Ferrie L, et al.

36. Erlotinib for the treatment of relapsed non-small cell lung cancer.

    By McLeod C, Bagust A, Boland A, Hockenhull J, Dundar Y, Proudlove C, et al.

37. Cetuximab plus radiotherapy for the treatment of locally advanced squamous cell carcinoma of the head and neck.

    By Griffin S, Walker S, Sculpher M, White S, Erhorn S, Brent S, et al.

38. Infliximab for the treatment of adults with psoriasis.

    By Loveman E, Turner D, Hartwell D, Cooper K, Clegg A

39. Psychological interventions for postnatal depression: cluster randomised trial and economic evaluation. The PoNDER trial.

    By Morrell CJ, Warner R, Slade P, Dixon S, Walters S, Paley G, et al.

40. The effect of different treatment durations of clopidogrel in patients with non-ST-segment elevation acute coronary syndromes: a systematic review and value of information analysis.

    By Rogowski R, Burch J, Palmer S, Craigs C, Golder S, Woolacott N.

41. Systematic review and individual patient data meta-analysis of diagnosis of heart failure, with modelling of implications of different diagnostic strategies in primary care.

    By Mant J, Doust J, Roalfe A, Barton P, Cowie MR, Glasziou P, et al.

42. A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial.

    By Gray AJ, Goodacre S, Newby DE, Masson MA, Sampson F, Dixon S, et al. , on behalf of the 3CPO study investigators.

43. Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

    By Ara R, Pandor A, Stevens J, Rees A, Rafia R.

44. Adefovir dipivoxil and pegylated interferon alpha for the treatment of chronic hepatitis B: an updated systematic review and economic evaluation.

    By Jones J, Shepherd J, Baxter L, Gospodarevskaya E, Hartwell D, Harris P, et al.

45. Methods to identify postnatal depression in primary care: an integrated evidence synthesis and value of information analysis.

    By Hewitt CE, Gilbody SM, Brealey S, Paulden M, Palmer S, Mann R, et al.

46. A double-blind randomised placebo-controlled trial of topical intranasal corticosteroids in 4- to 11-year-old children with persistent bilateral otitis media with effusion in primary care.

    By Williamson I, Benge S, Barton S, Petrou S, Letley L, Fasey N, et al.

47. The effectiveness and cost-effectiveness of methods of storing donated kidneys from deceased donors: a systematic review and economic model.

    By Bond M, Pitt M, Akoh J, Moxham T, Hoyle M, Anderson R.

48. Rehabilitation of older patients: day hospital compared with rehabilitation at home. A randomised controlled trial.

    By Parker SG, Oliver P, Pennington M, Bond J, Jagger C, Enderby PM, et al.

49. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis.

    By Renfrew MJ, Craig D, Dyson L, McCormick F, Rice S, King SE, et al.

50. The clinical effectiveness and cost-effectiveness of bariatric (weight loss) surgery for obesity: a systematic review and economic evaluation.

    By Picot J, Jones J, Colquitt JL, Gospodarevskaya E, Loveman E, Baxter L, et al.

51. Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness.

    By Daniels J, Gray J, Pattison H, Roberts T, Edwards E, Milner P, et al.

52. Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

    By Honest H, Forbes CA, Durée KH, Norman G, Duffy SB, Tsourapas A, et al.

53. The effectiveness and cost-effectiveness of cochlear implants for severe to profound deafness in children and adults: a systematic review and economic model.

    By Bond M, Mealing S, Anderson R, Elston J, Weiner G, Taylor RS, et al.

54. Gemcitabine for the treatment of metastatic breast cancer.

    By Jones J, Takeda A, Tan SC, Cooper K, Loveman E, Clegg A.

55. Varenicline in the management of smoking cessation: a single technology appraisal.

    By Hind D, Tappenden P, Peters J, Kenjegalieva K.

56. Alteplase for the treatment of acute ischaemic stroke: a single technology appraisal.

    By Lloyd Jones M, Holmes M.

57. Rituximab for the treatment of rheumatoid arthritis.

    By Bagust A, Boland A, Hockenhull J, Fleeman N, Greenhalgh J, Dundar Y, et al.

58. Omalizumab for the treatment of severe persistent allergic asthma.

    By Jones J, Shepherd J, Hartwell D, Harris P, Cooper K, Takeda A, et al.

59. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin’s lymphoma.

    By Boland A, Bagust A, Hockenhull J, Davis H, Chu P, Dickson R.

60. Adalimumab for the treatment of psoriasis.

    By Turner D, Picot J, Cooper K, Loveman E.

61. Dabigatran etexilate for the prevention of venous thromboembolism in patients undergoing elective hip and knee surgery: a single technology appraisal.

    By Holmes M, C Carroll C, Papaioannou D.

62. Romiplostim for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a single technology appraisal.

    By Mowatt G, Boachie C, Crowther M, Fraser C, Hernández R, Jia X, et al.

63. Sunitinib for the treatment of gastrointestinal stromal tumours: a critique of the submission from Pfizer.

    By Bond M, Hoyle M, Moxham T, Napier M, Anderson R.

64. Vitamin K to prevent fractures in older women: systematic review and economic evaluation.

    By Stevenson M, Lloyd-Jones M, Papaioannou D.

65. The effects of biofeedback for the treatment of essential hypertension: a systematic review.

    By Greenhalgh J, Dickson R, Dundar Y.

66. A randomised controlled trial of the use of aciclovir and/or prednisolone for the early treatment of Bell’s palsy: the BELLS study.

    By Sullivan FM, Swan IRC, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al.

67. Lapatinib for the treatment of HER2-overexpressing breast cancer.

    By Jones J, Takeda A, Picot J, von Keyserlingk C, Clegg A.

68. Infliximab for the treatment of ulcerative colitis.

    By Hyde C, Bryan S, Juarez-Garcia A, Andronis L, Fry-Smith A.

69. Rimonabant for the treatment of overweight and obese people.

    By Burch J, McKenna C, Palmer S, Norman G, Glanville J, Sculpher M, et al.

70. Telbivudine for the treatment of chronic hepatitis B infection.

    By Hartwell D, Jones J, Harris P, Cooper K.

71. Entecavir for the treatment of chronic hepatitis B infection.

    By Shepherd J, Gospodarevskaya E, Frampton G, Cooper K.

72. Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal.

    By Stevenson M, Pandor A.

73. Rivaroxaban for the prevention of venous thromboembolism: a single technology appraisal.

    By Stevenson M, Scope A, Holmes M, Rees A, Kaltenthaler E.

74. Cetuximab for the treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck.

    By Greenhalgh J, Bagust A, Boland A, Fleeman N, McLeod C, Dundar Y, et al.

75. Mifamurtide for the treatment of osteosarcoma: a single technology appraisal.

    By Pandor A, Fitzgerald P, Stevenson M, Papaioannou D.

76. Ustekinumab for the treatment of moderate to severe psoriasis.

    By Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A.

77. Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model.

    By Chambers D, Epstein D, Walker S, Fayter D, Paton F, Wright K, et al.

78. Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation.

    By Chen Y-F, Jowett S, Barton P, Malottki K, Hyde C, Gibbs JSR, et al.

79. Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY) – a pharmacoepidemiological and qualitative study.

    By Wong ICK, Asherson P, Bilbow A, Clifford S, Coghill D, R DeSoysa R, et al.

80. ARTISTIC: a randomised trial of human papillomavirus (HPV) testing in primary cervical screening.

    By Kitchener HC, Almonte M, Gilham C, Dowie R, Stoykova B, Sargent A, et al.

81. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic evaluation.

    By Black C, Clar C, Henderson R, MacEachern C, McNamee P, Quayyum Z, et al.

82. Randomised preference trial of medical versus surgical termination of pregnancy less than 14 weeks’ gestation (TOPS).

    By Robson SC, Kelly T, Howel D, Deverill M, Hewison J, Lie MLS, et al.

83. Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

    By Jeffcoate WJ, Price PE, Phillips CJ, Game FL, Mudge E, Davies S, et al.

84. VenUS II: a randomised controlled trial of larval therapy in the management of leg ulcers.

    By Dumville JC, Worthy G, Soares MO, Bland JM, Cullum N, Dowson C, et al.

85. A prospective randomised controlled trial and economic modelling of antimicrobial silver dressings versus non-adherent control dressings for venous leg ulcers: the VULCAN trial.

    By Michaels JA, Campbell WB, King BM, MacIntyre J, Palfreyman SJ, Shackley P, et al.

86. Communication of carrier status information following universal newborn screening for sickle cell disorders and cystic fibrosis: qualitative study of experience and practice.

    By Kai J, Ulph F, Cullinan T, Qureshi N.

87. Antiviral drugs for the treatment of influenza: a systematic review and economic evaluation.

    By Burch J, Paulden M, Conti S, Stock C, Corbett M, Welton NJ, et al.

88. Development of a toolkit and glossary to aid in the adaptation of health technology assessment (HTA) reports for use in different contexts.

    By Chase D, Rosten C, Turner S, Hicks N, Milne R.

89. Colour vision testing for diabetic retinopathy: a systematic review of diagnostic accuracy and economic evaluation.

    By Rodgers M, Hodges R, Hawkins J, Hollingworth W, Duffy S, McKibbin M, et al.

90. Systematic review of the effectiveness and cost-effectiveness of weight management schemes for the under fives: a short report.

    By Bond M, Wyatt K, Lloyd J, Welch K, Taylor R.

91. Are adverse effects incorporated in economic models? An initial review of current practice.

    By Craig D, McDaid C, Fonseca T, Stock C, Duffy S, Woolacott N.