A randomised controlled multicentre trial of treatments for adolescent anorexia nervosa including assessment of cost-effectiveness and patient acceptability - the TOuCAN trial

Article history

The research reported in this issue of the journal was commissioned by the HTA programme as project number 97/42/02. The contractual start date was in January 2000. The draft report began editorial review in July 2009 and was accepted for publication in October 2009. 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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2010 Queen’s Printer and Controller of HMSO

Anorexia nervosa in young people

Anorexia nervosa (AN) is a complex eating disorder, generally developing in adolescence or young adulthood but sometimes in late childhood. It is relatively rare at 12 years, but the prevalence rises with age, reportedly reaching about one in 200 adolescent girls at 16 years. The highest incidence rates are for females aged 15–19 years, who represent approximately 40% of all identified cases. 1 Incidence and prevalence rates of AN in males are more rarely reported, but it has been noted that where they are, the female to male ratio is around 11 : 1 overall1 but it appears to be somewhat lower in adolescents,2 with a more equal sex ratio at the younger end of the spectrum.

Anorexia nervosa appears to have become more common over recent decades, but the apparent increase could well be the result of greater help-seeking, better detection and changes in diagnostic practice rather than of any true increase in the incidence of the disorder. 3 The best evidence for this comes from Rochester, MN, USA. 4 This study suggested an increase in incidence of 36% in adolescent females every 5 years from 1950 to 1984. Anorexia nervosa is currently the most prevalent disorder within inpatient child and adolescent mental health services. 5

It is thought that eating disorders may have changed over time, particularly in the increasing ratio of the purging form of AN to the restricting form. Anorexia nervosa used to be seen as a middle-class disorder of the white, western world. This is no longer the case, although uncertainties exist as to whether there has been a change in identification of cases in different cultures or whether the condition has spread to black and ethnic minority populations and to developing nations as they have taken on western culture and lifestyles.

Anorexia nervosa has the highest mortality rate of any psychiatric disorder in the UK; with patients with AN being 12 times more likely to die than women of a similar age in the general population. 6 The mortality rate among adolescents is low. Most deaths are either a direct result of medical complications or due to suicide.

Clinical features

Anorexia nervosa is a syndrome comprising a range of physical, psychological and behavioural features. These usually have an impact on social functioning and eventually their effects pervade most areas of the young person’s life.

Four features are required to make a diagnosis:

• overevaluation of the importance of weight and shape (this is often expressed as an intense fear of becoming fat and is sometimes referred to as a distortion of body image)

• maintenance of an unduly low bodyweight [that is less than 85% of that expected, or a body mass index (BMI) below the second percentile for age]

• active control of weight by dietary restriction, exercise, vomiting or purging

• a widespread endocrine disturbance involving the hypothalamic–pituitary–gonadal axis (this is manifest as amenorrhoea in postpubertal females, as pubertal delay in pubescent females and as impotence and lack of sexual interest in males).

The central features are essentially the same in both sexes; those with AN judge their self-worth largely, or even exclusively, in terms of their shape and weight and their ability to control them. This results in a pursuit of weight loss and an intense fear of weight gain and fatness. Most of the other features are secondary to this cognitive abnormality and its consequences and there is a complex relationship between cognition, behaviour and the physical features. To the extent that this pursuit of a low weight is successful, weight control is seen as necessary rather than problematic. Successful dieting therefore tends to be viewed positively and, as a consequence, young people with AN generally have low motivation to change.

In AN a very low weight may be attained through severe and selective restriction of food intake with self-induced vomiting and other forms of weight-control behaviour (such as the misuse of laxatives or diuretics) practised by a subgroup. Depressive and anxiety features, irritability, lability of mood, impaired concentration, loss of sexual interest and obsessional symptoms are frequently present. Typically these features get worse as weight is lost and improve to a large extent with weight restoration. Interest in the outside world also declines with the result that most become socially withdrawn and isolated. As bodyweight is maintained at least 15% below that expected, pubertal development is stunted or reversed. This results in either a delay in the menarche or secondary amenorrhoea in those who have completed puberty.

Negative physical outcomes such as failure to reach expected height, stunted breast development and reduced bone density are often reported. In the longer term, eating disorders may have an impact on pregnancy and motherhood. In those recovering from AN, fertility problems, spontaneous abortion, prematurity and small-for-gestational-age babies are regularly reported, as are elevated rates of infant mortality. 7,8

A systematic review of 119 outcome studies of patients across the age range,9 found high rates of anxiety disorders and affective disorders at long-term follow-up as well as substance misuse. Full long-term recovery was reported for 45.1%, a fair outcome for 35%, whereas 19.8% had a chronic course.

Treatment of anorexia nervosa

There has been surprisingly little research on the treatment of AN but most of this work has concerned adolescents. 10,11. Recent systematic reviews11–13 have drawn attention to the shortage of quality, adequately-powered treatment trials for anorexia nervosa. The National Institute for Clinical Excellence [now National Institute for Health and Clinical Excellence (NICE)] guidelines made treatment recommendations classified from A (the strongest) to C (the weakest), based on the strength of evidence. In considering the full range of psychological therapies, physical (including pharmacological) treatment and service settings, it was unable to make a single Grade A treatment recommendation across the age range. 11 Guidelines on the management of child and adolescent eating disorders are therefore based mainly on expert clinical opinion and cohort studies rather than on randomised clinical trials. A number of academic bodies have published consensus guidelines, some specifically in relation to the management of children and adolescents. There is much greater emphasis in these on physical rather than other aspects of management.

Service issues

Various treatment settings have been used to manage AN. The main ones being outpatient, day-patient or partial hospitalisation, and inpatient treatment; and within these settings a variety of interventions may be provided, physical, psychological or both. To complicate matters, patients may move from one setting to another, and within any one setting often more than one treatment is employed.

Inpatient treatment is used differently in different places; for example, it is common in some countries but unusual in others, and length of stay also varies markedly. 25 Such differences are not evidence-based because inpatient treatment has received scant research attention. For example, not only are the indications for hospitalisation not established, but the specific goals are not agreed nor is it known how best to achieve them. At best, there is modest evidence from cohort studies to support a focus on eating and an emphasis on weight regain. Comparisons of flexible behavioural programmes with more rigid ones have either yielded no significant differences in the rate of weight regain or have favoured the more flexible regimes. There is no evidence that drug treatment significantly enhances weight regain.

Whatever the place of inpatient and day-patient treatment, outpatient treatment is the mainstay of the treatment of AN. Outpatient treatment is the sole treatment for many patients, and even if patients receive inpatient or day-patient treatment, it is usually followed by outpatient treatment. The choice of setting used to treat young people with AN has tended to be based on clinical judgement and the availability of different models of service rather than research evidence. Debate about the merits of inpatient management frequently fails to distinguish between (often brief) medical admission and longer psychiatric admission, aimed at a combination of weight restoration, normal eating and psychological change. Most young people with AN can be managed on an outpatient basis, with inpatient care being only required for a minority, where there are serious complications related to comorbid diagnoses, or where there is high physical or psychiatric risk. 26 When admission is deemed necessary this may be to a paediatric ward, a general child or adolescent psychiatric unit, or to a specialist eating disorder service.

Research in the area of service provision is limited. There is one systematic review summarising what is known about the relative effectiveness of inpatient and outpatient care across the age range. 27 However, the review was based on only one small RCT with a 5-year follow-up, often referred to as the St Georges study,28,29 plus a number of very varied cohort series, making it difficult to draw meaningful conclusions. The main conclusions of the systematic review are that outpatient treatment for AN at a specialist tertiary referral eating disorder service was as effective as inpatient treatment in those not so severely ill as to warrant emergency intervention, and that outpatient care is in general cheaper than inpatient care.

It is widely believed that there are advantages in treating severe AN within a specialised tertiary eating disorder service compared with less specialised secondary services. Both competence and confidence tend to develop in settings where such treatment is a regular and ongoing activity.

User satisfaction

A crucial issue in AN concerns the patient’s attitude to the disorder. There is generally some ambivalence and at times determined opposition to treatment. Controversy also exists over the role of treatments given without the patient’s consent. Patients may in certain circumstances be detained under the Mental Health Act (1983) but the NICE guideline expressed concern about the lack of clarity and openness around the treatment of young people when given on the basis of parental consent alone. 11

Patient satisfaction has become increasingly important to the UK health-care industry and evaluation of the quality of health-care provision is essential for the improvement of services. However, there is a lack of clarity with regards to the definitions of service quality and satisfaction. Service quality and patient satisfaction are linked, indeed a South Korean study30 recently found that 62% of the total variation in patient satisfaction was explained by service quality dimensions. Clearly when expectations of a service are greater than perceived performance, then quality will be judged as less satisfactory and dissatisfaction will be high. Those with eating disorders have been said to represent a unique group of health-care consumers among whom dissatisfaction tends to be high. 31 Furthermore, the source of negative commentary is often around activities and structures viewed as essential to traditional treatments. 32

Economic aspects

As well as being associated with severe physical, psychological and social impairments and high levels of mortality,11 AN places a significant cost-burden on young people, their families, health services and the wider society. 33,34 Inpatient admission for young people with AN is particularly disruptive to school, family and social life, and is an expensive option, yet evidence to support its cost-effectiveness is lacking. 11,35

Rationale for the current trial

The recent research literature (confirmed during the course of the study by the NICE guideline) suggested that despite lengthy inpatient psychiatric treatment being commonly recommended as the ‘gold standard’ treatment for the condition,36 there was little evidence to support this practice. The one small RCT of service setting showed no advantage of inpatient management over outpatient care for adults,29 whereas our earlier cohort study37 showed poor outcomes for adolescent inpatients. It seemed likely that inpatient management might be cost-ineffective. We were also aware of the low levels of satisfaction reported in some studies with inpatient management. Although, (in the course of this study) the NICE guideline recommended treatment in specialist settings, this has often been confused with treatment in homogeneous units in which all patients have the same condition. We therefore wished to explore the effectiveness of specialist services as described by the Eating Disorders section of the Royal College of Psychiatrists; that is, services with a dedicated, trained, multidisciplinary team treating a significant number of cases each year.

We report here a large population-based RCT of the three most common treatments available for adolescents with AN in the UK to compare the relative merits of inpatient psychiatric treatment and two forms of outpatient management, namely ‘treatment as usual’ in generic CAMHS, and a specialist multimodal multidisciplinary programme developed for the study.

Trial procedures

Measures

Data analytic strategy and methods

Economic evaluation methods

Baseline characteristics

Clinical features

Table 2 and Table 3 show the presenting features of the three randomised treatment arms and the preference group. They were generally a moderately to severely ill group (mean weight for height 80.0%, lowest 59.9%). Eight cases had a weight for height above the diagnostic threshold for AN. Of these, four were included because they lost significant weight in the 4 weeks following assessment, or they had previously attained a greater height percentile, suggesting stunting of growth. While four others with borderline weights were included because they fulfilled the other criteria plus significant (> 15% and generally > 20%) weight loss with amenorrhoea. Five cases were sporadically menstruating, but at < 85% weight for height.

TABLE 2 - Categorical baseline characteristics by treatment group: frequency (%)

	General CAMHS (n = 55)	Specialist outpatient (n = 55)	Specialist inpatient (n = 57)	Preference (n = 48)
Site
Mersey	29 (53)	25 (45)	33 (58)	31 (65)
North-west	26 (47)	30 (55)	24 (42)	17 (35)
Female	51 (93)	51 (93)	51 (89)	46 (96)
Subtype
Restrictor	44 (80)	42 (76)	41 (72)	35 (73)
Binge–purger	11 (20)	13 (24)	16 (28)	13 (27)
History (months)
< 15	36 (65)	34 (62)	41 (72)	19 (40)
> 15	18 (33)	16 (29)	13 (23)	26 (54)
Not known	1 (2)	5 (9)	3 (5)	3 (6)

TABLE 3 - Quantitative baseline characteristics by treatment group

Primary outcome measure at baseline.

	General CAMHS			Specialist outpatient			Specialist inpatient			Preference
	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n	Mean	(SD)	n
Age (years)	14.97	(1.40)	55	15.09	(1.22)	55	14.88	(1.46)	57	15.40	(1.76)	48
Morgan–Russell Scales
A (Food intake)	3.09	(1.63)	55	3.36	(1.99)	55	3.30	(1.74)	57	2.67	(2.16)	48
B (Menstruation)	1.00	(2.41)	48	0.80	(2.14)	50	0.87	(2.52)	46	0.74	(2.00)	43
C (Mental state)	5.31	(2.18)	55	5.24	(1.87)	55	5.47	(1.95)	57	5.33	(2.08)	48
D (Psychosexual state)	5.53	(2.65)	55	5.84	(2.82)	55	6.57	(2.87)	56	5.64	(3.26)	45
E (Socioeconomic state)	7.84	(1.98)	55	7.21	(2.99)	55	8.11	(2.17)	57	7.17	(2.68)	48
MRAOS (average of all scales)a	4.67	(1.27)	55	4.56	(1.46)	55	5.05	(1.46)	57	4.38	(1.59)	48
Weight for height (%)	78.80	(7.86)	55	77.14	(8.10)	55	78.16	(8.08)	57	74.82	(9.30)	48
Body mass index	15.48	(1.60)	55	15.25	(1.58)	55	15.29	(1.65)	57	14.85	(1.78)	48
EDI-2 total	88.48	(51.36)	52	86.52	(47.53)	54	89.61	(44.52)	56	89.76	(45.76)	41
MFQ total	32.36	(16.12)	53	30.09	(14.70)	54	32.55	(14.60)	56	32.20	(14.67)	44
FAD-GF	2.13	(0.59)	52	2.12	(0.53)	54	2.08	(0.49)	56	2.08	(0.58)	41
HoNOSCA
Clinician-rated	20.04	(5.72)	55	20.71	(7.50)	55	20.04	(5.63)	57	20.98	(5.94)	48
Self-rated	16.46	(9.95)	54	17.40	(9.88)	53	15.64	(9.54)	53	15.70	(9.89)	43

There were no significant differences between groups on any variable including length of history. For the EDI, MFQ, FAD and HoNOSCA a higher score indicates greater difficulty, whereas the Morgan–Russell Scales indicate greater clinical severity by a lower score. Characteristics of all four groups were similar, although the non-randomised preference group was slightly older, contained more patients with a longer history of eating disorder and tended to have worse morbidity at baseline with a lower % weight for height and MRAOS.

Adherence to treatment allocation and withdrawals

Despite all randomised subjects agreeing to randomisation at the point of giving signed informed consent, adherence to allocated treatment was only 67% and varied between groups (Figure 1). To a large extent this lack of adherence is in the nature of the condition and the attitude of patients with AN to treatment. Explanation of the failure of adherence was as follows:

• Inpatient treatment adherence rate = 28/59 (49.1%) (defined as a minimum 4-week inpatient stay). In most cases, those failing to adhere agreed initially to admission and then bargained their way out by achieving a small weight gain in the short time between randomisation and admission. Mean length of stay for those admitted was 15.2 weeks.

• Specialist outpatient adherence rate = 41/57 (76.5%) (defined as a minimum of six attendances). Of the remainder, 10 changed their mind and opted for general CAMHS treatment (generally because of travelling distance), three were admitted before treatment could start and one dropped out of all treatment.

• General CAMHS adherence rate = 38/57 (71.1%) [defined as attending general CAMHS and no other treatment (beyond possibly specialist second opinion) in the initial 6-month phase]. Two of the remainder had no treatment, four opted for specialist outpatient treatment, while 11 were referred to an alternative by clinician preference (10 inpatient, one specialist outpatient).

FIGURE 1.

TOuCAN trial – recruitment.

Clinical outcomes

Comparison of inpatient with outpatient treatment

Table 6 and Table 7 summarise the outcome for the quantitative outcome measures and give confidence intervals for the two planned comparisons.

When a linear mixed model was fitted including the assessment point (1, 2, 5 years) with treatment–group interaction, there were no interactions between assessment and treatment for the primary outcome measure (MRAOS), nor for the secondary outcome measures (Table 8) for this comparison. When the model was refitted without an interaction there was no main effect of inpatient treatment for MRAOS or the secondary measures. In a further analysis, not presented here, there was no treatment by site interaction. No further subgroup analyses of potential moderators have been carried out.

The analyses suggest no advantage for inpatient over outpatient treatment.

Comparison of specialist treatment with general CAMHS

In the comparison of specialist services with general CAMHS, there was no interaction between assessment and treatment in the linear mixed model analyses for the primary outcome measure except for the secondary outcome measures % weight for height and FAD-GF. In both cases, the direction of the interactions suggested that the outcome for specialist treatments tended to improve relative to general CAMHS over time. There was an increased effect of specialist treatment relative to general CAMHS between consecutive assessments of 2.80 (95% CI 0.31 to 5.29 p = 0.027). At the 1-year and 2-year follow-ups the general CAMHS treatment gave slightly better (but non-significant) outcomes than the two specialist treatments for % weight for height.

Patients in the specialist treatments reported better outcomes at 5 years than those on CAMHS treatment (p = 0.02, see Table 7). For FAD-GF specialist treatments reported a better outcome at 5 years, but this finding was not statistically significant. It should be noted, that the proportion of subjects followed up to 5 years is low and varied between treatment arms [general CAMHS 36% (20/57), specialist outpatient 58% (31/57), specialist inpatient 42% (24/59)], so that differences between treatments at 5 years may therefore be based on selection effects with the follow-up influenced by randomisation; as the reduced follow-up in the CAMHS arm may arise because of the reduced contact of trial subjects with specialist services.

When the model was refitted without an interaction there was a significant main effect of specialist treatment compared with general CAMHS treatment for MFQ. Averaging across follow-up assessments MFQ was 5.94 points (95% CI 1.56 to 10.35, p = 0.008) lower (better outcome) in specialist services than general CAMHS. This difference is also apparent in Table 7 with the difference between specialist treatment and general CAMHS being 3.6, 5.7 and 7.2 at 1, 2 and 5 years follow-up, respectively. There were no other differences between groups.

There was no treatment by site interaction and no other subgroup analyses were carried out.

Diagnostic outcome category

Table 9 and Figure 2 show the diagnostic outcome category at years 1, 2 and 5. These are based on the categories employed in the Maudsley studies18,21,37 employing a high threshold for assigning recovery. A good outcome indicates a full recovery from AN (weight above 85% of expected, return of menstruation, bingeing/purging no greater than once per month). A poor outcome was indicated if weight was not above 85% or the young person was still being treated as an inpatient for AN. The intermediate category comprises those whose weight had risen to within the normal range, but without return of menstruation, with bingeing–purging at a frequency greater than monthly, or considerable residual concerns about weight and shape scored on Morgan–Russell scale A. At 1 year, 18% had fully recovered, 38% still had diagnostic AN. By 2 years there was an overall good outcome for 33%, but 27% still had the condition.

FIGURE 2.

Percentage good outcome (cases with known outcome).

Table 10 summaries the longitudinal marginal model analysis using robust standard errors. There were no statistically significant differences between inpatient and outpatient treatments. In the comparison of specialist treatment with general CAMHS treatment there was slight evidence of a time with treatment interaction (0 = 0.66). From Table 10 it can be seen that general CAMHS did better than specialist treatments at 1 year (Common Odds Ratio 0.56, 95% CI 0.29 to 1.01 p = 0.05), having fewer poor outcomes, whereas at 5 years the Common Odds Ratio tended to favour specialist treatment (1.54, 95% CI 0.61 to 3.93) although not significantly (p = 0.39). There was no treatment by site interaction and no other subgroup analyses were carried out.

Adherence to treatment allocation and outcome

The trial aimed to compare randomisation to specialist inpatient treatment and specialist outpatient treatment with randomisation to general CAMHS treatment. However, as we have discussed, adherence to the allocated treatment was poor for the inpatient arm. In the first year of the trial, specialist inpatient treatment at one of the four centres was received by 49% (28/59) of subjects randomised to this treatment and 20% (23/110) of those randomised to general CAMHS or specialist treatment. Assuming that there are no subjects who will always opt for the opposite of their randomly assigned treatment, one can argue that only 29% of patients (49% minus 20%) accepted randomisation to specialist inpatient treatment because 20% would have received this irrespective of random allocation and 53% (29/59) did not receive it.

Of those patients randomised to specialist outpatient treatment at the two specialist outpatient centres, 75% (41/57) received specialist outpatient treatment, whereas only 18% (20/112) of patients randomised to either general CAMHS or specialist inpatient received this. Hence, randomisation to specialist outpatient treatment was more likely to be determined by randomisation than specialist inpatient treatment, with 57% (75% minus 18%) accepting randomisation of this option. Allocation to specialist outpatient treatment led to 77% of the sample receiving some form of specialist treatment whereas only half of those assigned to specialist inpatient treatment received it.

Adherence to allocated treatment did have a significant bearing on outcome, though a number of issues, including those above, mean that caution is advised in interpreting the findings.

Examining the outcome of those allocated to inpatient treatment reveals that adherence to this treatment was poor (49%, 28 out of 59) and so in theory this might have compromised the effectiveness of this intervention. At baseline, Table 12 demonstrates that, on the measures used, there was little difference between the two subgroups (adherers and non-adherers), though those who were admitted were on average 6 months younger and showed a reduced food intake (Morgan–Russell Scale A).

TABLE 12 - Outcomes of inpatients adhering to treatment and those refusing admission, postrandomisation

Adjusted for baseline.

Outcome measure	Baseline					1 year							2 years
	Adherers (n = 28)		Non-adherers (n = 29)			Adherers (n = 26)		Non-adherers (n = 26)		Difference between non-adherers and adherers			Adherers (n = 25)		Non-adherers (n = 27)		Difference between non-adherers and adherers
	Mean	(SD)	Mean	(SD)	p	Mean	(SD)	Mean	(SD)	Diff.a	95% CI	p	Mean	(SD)	Mean	(SD)	Diffa	95% CI	p
Body mass index (BMI)	14.8	(1.8)	15.8	(1.4)	0.026	17.2	(2.2)	17.9	(2.1)	0.02	(– 1.07 to 1.11)	0.97	18.3	(3.0)	19.0	(2.6)	0.39	(– 1.20 to 1.97)	0.63
% Weight for height	76.5	(8.3)	79.7	(7.6)	0.134	85.8	(9.6)	87.5	(10.3)	–0.06	(– 5.15 to 5.04)	0.98	88.9	(14.4)	91.9	(12.4)	1.82	(– 5.79 to 9.44)	0.63
EDI-2
Drive for thinness	11.0	(7.1)	11.1	(7.5)	0.985	9.6	(8.4)	4.5	(5.6)	–4.47	(– 8.65 to – 0.28)	0.04	3.5	(4.1)	4.6	(6.1)	1.45	(– 1.59 to 4.49)	0.34
Body dissatisfaction	14.1	(8.9)	16.3	(7.5)	0.317	15.0	(11.4)	8.7	(8.6)	–6.78	(– 12.31 to – 1.24)	0.02	8.4	(9.2)	8.6	(9.3)	–0.82	(– 6.09 to 4.45)	0.76
Total	89.9	(47.0)	89.3	(42.7)	0.962	74.6	(55.0)	48.5	(49.0)	–21.99	(– 52.31 to 8.33)	0.15	43.1	(33.2)	38.2	(39.3)	–4.66	(– 25.7 to 16.4)	0.66
MFQ Total	33.9	(13.8)	31.3	(15.5)	0.509	24.5	(17.0)	12.7	(12.3)	–10.28	(– 19.03 to – 1.52)	0.03	20.1	(14.2)	12.3	(14.1)	–7.10	(– 15.2 to 1.00)	0.08
HoNOSCA
Clinician-rated	21.0	(6.7)	19.1	(4.3)	0.224	17.2	(7.0)	11.4	(6.7)	–5.27	(– 9.07 to –1.47)	0.01	16.8	(9.9)	11.9	(7.9)	–3.48	(– 8.17 to 1.21)	0.14
Self-rated	17.3	(10.2)	13.8	(8.6)	0.177	12.3	(8.8)	5.3	(6.0)	–5.67	(– 10.71 to – 0.63)	0.03	9.3	(9.7)	6.2	(7.3)	–1.59	(– 6.41 to 3.24)	0.51
Morgan–Russell Scales
Scale A (Food intake)	2.7	(1.5)	3.9	(1.8)	0.009	5.8	(2.9)	8.1	(2.6)	1.61	(0.10 to 3.13)	0.04	6.5	(3.5)	8.4	(2.8)	1.62	(– 0.25 to 3.48)	0.09
Scale B (Menstruation)	0.7	(2.0)	1.0	(3.0)	0.645	4.6	(5.3)	7.3	(5.5)	3.24	(– 0.24 to 6.72)	0.07	6.2	(5.5)	9.0	(4.5)	2.67	(– 0.50 to 5.84)	0.10
Scale C (Mental state)	5.0	(1.8)	5.9	(2.0)	0.071	5.8	(2.8)	8.1	(2.3)	1.89	(0.49 to 3.28)	0.01	7.0	(2.9)	8.9	(3.2)	1.03	(– 0.57 to 2.63)	0.20
Scale D (Psychosexual)	6.6	(3.3)	6.5	(2.4)	0.870	6.7	(3.7)	8.4	(2.9)	1.66	(– 0.20 to 3.52)	0.08	8.0	(3.8)	9.3	(3.1)	1.31	(– 0.60 to 3.22)	0.17
Scale E (Socioeconomic state)	7.8	(2.2)	8.4	(2.1)	0.336	8.4	(2.1)	10.4	(1.8)	1.90	(0.81 to 2.98)	0.001	9.1	(2.9)	9.6	(2.7)	0.35	(– 1.21 to 1.92)	0.65
Average outcome (Average of all scales)	4.8	(1.5)	5.3	(1.4)	0.127	6.3	(2.5)	8.6	(1.8)	2.02	(0.83 to 3.22)	0.001	7.4	(2.6)	9.0	(2.3)	1.46	(0.05 to 2.87)	0.04

For the two outpatient treatment arms there was a notably better outcome for those who fully adhered to treatment compared with those failing to adhere or later transferring away from the allocated treatment. Specifically, for general CAMHS treatment, only one out of 17 admitted for inpatient treatment had a good outcome at 1 year, whereas for the specialist outpatient programme, none of the 14 who initially failed to adhere to the allocated programme had a good outcome, nor any of 14 subsequently admitted to inpatient treatment (Table 13). At 2 years, of 17 allocated to CAMHS who were admitted to hospital, two had a good outcome whereas for the specialist outpatient programme, 13 found their way into inpatient management, of whom only one had a good outcome.

TABLE 13 - Categorical outcomes at 1 and 2 years for adherers and non-adherers

Ordinal logistic regression, 1 year p = 0.22; 2 years p = 0.89.

	1 year				2 years
	Good	Intermediate	Poor	Not known (alive)	Good	Intermediate	Poor	Not known (alive)
General CAMHS
Adherers
Full	8	19	4		15	12	3	1
Subsequently admitted	0	3	4		0	0	7
Total (n = 38)	8	22	8		15	12	10	1
Non-adherers
Treated as outpatient	1	2	1	1	2	2	1
Treated as inpatient	1	6	3		2	6	2
Untreated	0	1	1		1	0	1
Total (n = 17)	2	9	5	1	5	8	4
Total	10 (18%)	31 (56%)	13 (24%)	1(2%)	20(36%)	20(36%)	14 (26%)	1 (2%)
Specialist outpatient
Adherers
Full	8	12	11		11	15	5
Subsequently admitted	0	3	7		0	7	2	1
Total (n = 41)	8	15	18		11	22	7	1
Non-adherers
Treated as outpatient	0	6	3		1	5	3
Treated as inpatient	0	1	3	1	1	1	2	1
Total (n = 14)	0	7	6	1	2	6	5	1
Total	8 (15%)	22 (40%)	24 (44%)	1 (2%)	13(24%)	28(51%)	12 (22%)	2 (4%)
Inpatient
Adherers (n = 28)	3	9	15	1	6	9	11	2
Non-adherers (n = 29)	9	9	11		13	8	6	2
Total	12 (21%)	18 (32%)	26 (46%)	1 (2%)	19(33%)	17 (30%)	17 (30%)	4 (7%)

Below, a predictor model is developed for prediction of admission in year 1 among subjects not randomised to inpatient treatment. This can be applied to subjects randomised to inpatient treatment to estimate the probability that each subject would have been admitted. Figure 3 illustrates the probability of admission according to initial adherence to randomisation to admission. Without randomisation, those subjects who initially adhere to allocation to hospital treatment had a high probability of receiving inpatient treatment. Thirty-eight per cent of adherers would have been admitted whereas only 24% of non-adherers would have been admitted (Wilcoxon p = 0.007). Initial adherers to hospital treatment had a higher propensity to receive it, suggesting that they had a different prognosis. Tables 12 and 13 cannot therefore be interpreted as providing a valid comparison of inpatient and outpatient treatment and should be interpreted with caution.

FIGURE 3.

Graphs by initial adherence.

Table 13 demonstrates the relatively better outcome of non-adherers in terms of outcome category. By 2 years, there is a general improvement from the 1-year time point, but this is more marked for those who declined admission. There remains a better outcome on the main outcome measure for those declining admission compared with those who were admitted, even controlling for baseline variables (Table 12).

At 1-year follow-up, those not admitted were doing significantly better on the MRAOS (mean difference 2.0, 95% CI 0.8 to 3.2, p = 0.001) and virtually all self-report measures of psychopathology, including mood (all change scores controlled for baseline values).

Inpatient admission appears to be associated with continuing high rates of core abnormal cognitions, such as body dissatisfaction and drive for thinness, whereas those who declined admission made improvements in these areas, suggestive of early cognitive improvement in this subgroup.

Baseline predictors of service usage

As only 18% of cases had fully recovered by 1 year and clinical judgement was used to determine treatment beyond the initial 6 months of the trial; we were interested to explore what predicted non-randomised admission to hospital and the use of inpatient beds within the first 2 years, irrespective of treatment allocation and predictors of still being in treatment 1 and 2 years after assessment. Table 16 shows some of the categorical features of those 102 patients admitted to hospital. Admission was more likely in the Manchester site, for binge–purgers and for those with a longer history of illness. Table 17 shows that those admitted had a lower presenting MRAOS and % weight for height and higher self-rated measures of psychopathology. Table 18 provides the statistical analysis showing that % weight for height and self-rated mood were powerful predictors of admission, and that weight for height and EDI-2 total score predicted a shorter time to admission and a greater number of admissions. Table 19 and the associated scatter plot (Figure 4) show that there is a modest but significant association between presenting MRAOS and number of inpatient days in the first 2 years. This illustrates that 15 subjects spent more than 1 year in the first 2 years in hospital, all with a presenting MRAOS of less than four.

TABLE 16 - Frequency of admission by baseline characteristic

Table does not include subjects randomised to inpatient treatment and includes the preference patients.

	Frequency	%
Gender
Male	9/16	56%
Female	93/193	47%
Type
Restrictor	71/162	44%
Binge–purger	31/53	58%
History
< 18 months	64/142	45%
≥ 18 months	38/73	52%

TABLE 17 - Proportion of subjects that were admitted by baseline characteristic at admission

Table does not include subjects randomised to inpatient treatment and includes the preference patients.

Baseline characteristic	Not admitted			Admitted
	Mean	SD	n	Mean	SD	n
Age	15.17	1.32	89	15.10	1.64	69
MRAOS	4.95	1.31	89	4.02	1.43	69
Weight for height	78.8	7.1	89	74.7	9.6	69
EDI-2 Total	79.0	43.2	85	100.7	51.9	62
FAD-GF	2.07	0.55	85	2.18	0.58	62
MFQ Total	27.8	14.5	89	36.8	14.5	62
HoNOSCA-CR	18.9	6.4	89	22.7	5.8	69
HoNOSCA-SR	14.2	8.5	87	19.8	10.8	63

TABLE 18 - Baseline predictors of hospital admissions

Table does not include subjects randomised to inpatient treatment and includes the preference patients.

Admission	Reduced model			Full model
	Odds ratio	95% CI	p-value	Odds ratio	95% CI	p-value
Site	2.768	(1.308 to 5.855)	0.008	3.545	(1.406 to 8.939)	0.007
Weight for height	0.916	(0.873 to 0.961)	< 0.001	0.914	(0.857 to 0.975)	0.007
MFQ Total	1.056	(1.029 to 1.085)	< 0.001	1.031	(0.988 to 1.076)	0.161
Time to first admission	Hazard ratio	95% CI	p-value	Hazard ratio	95% CI	p-value
Site	3.630	(1.821 to 7.237)	< 0.001	3.899	(1.706 to 8.913)	0.001
Weight for height	0.905	(0.865 to 0.947)	< 0.001	0.907	(0.853 to 0.963)	0.002
EDI-2 Total	1.013	(1.006 to 1.020)	< 0.001	1.009	(0.997 to 1.022)	0.128
Number of inpatient admissions	Common odds	95% CI	p-value	Common odds	95% CI	p-value
Site	2.062	(1.056 to 4.027)	0.034	2.234	(0.995 to 5.013)	0.051
Weight for height	0.919	(0.880 to 0.959)	< 0.001	0.944	(0.895 to 0.996)	0.036
EDI-2 Total	1.012	(1.005 to 1.019)	0.001	1.005	(0.993 to 1.017)	0.458

TABLE 19 - Predictors of inpatient days within first 2 years

Inpatient days	Reduced model			Full model
	Common odds ratio	95% CI	p-value	Common odds ratio	95% CI	p-value
MRAOS	0.667	(0.484 to 0.918)	0.013	0.652	(0.371 to 1.146)	0.138

FIGURE 4.

Predictors of inpatient days within first 2 years from MRAOS.

At 1 year, 130 cases were still in treatment and at 2 years this number was 64. Table 20 shows the categorical breakdown of these cases, Table 21 shows the baseline values of those who are in treatment at the two time points and Table 22 the baseline predictors of still being in treatment. In particular, those who were the thinnest and had the highest self-rated cognitions on the EDI-2 at presentation were likely to be still in treatment at 2 years.

TABLE 20 - In treatment at 1 and 2 years by patient characteristics

	1 year		2 years
	n	%	n	%
Site
Mersey	58/116	50%	31/115	27%
North-west	55/96	57%	31/96	32%
Gender
Male	8/16	50%	3/16	19%
Female	105/196	54%	59/195	30%
Type
Restrictor	92/160	58%	49/159	31%
Binge–purger	21/52	40%	13/52	25%
History
< 18 months	78/142	55%	45/141	32%
≥ 18 months	35/70	50%	17/70	24%

TABLE 21 - Quantitative characteristics at baseline according to treatment at 1 and 2 years

	1 year						2 years
	No			Yes			No			Yes
	Mean	SD	n	Mean	SD	n	Mean	SD	n	Mean	SD	n
Age	15.37	1.35	99	14.79	1.52	113	15.27	1.40	149	14.53	1.52	62
MRAOS	5.20	1.40	99	4.23	1.34	113	4.91	1.39	149	4.12	1.46	62
Weight for height	78.5	7.6	99	76.4	9.0	113	78.0	8.0	149	75.7	9.3	62
EDI-2 Total	83.3	47.4	95	93.4	46.8	106	86.3	46.8	143	95.7	47.5	57
FAD-GF	2.07	0.55	95	2.13	0.55	106	2.11	0.53	143	2.10	0.59	57
MFQ Total	28.6	14.4	96	34.8	14.9	108	31.0	14.7	145	34.3	15.3	58
HoNOSCA-CR	18.8	6.0	99	21.7	6.1	113	20.0	6.2	149	21.3	6.3	62
HoNOSCA-SR	14.4	9.2	94	18.0	10.0	107	15.7	9.4	141	18.0	10.6	59

TABLE 22 - Baseline predictors of being in treatment at 1 and 2 years

	Reduced model			Full model
	Odds ratio	95% CI	p-value	Odds ratio	95% CI	p-value
1 year
Age	0.805	(0.648 to 1.001)	0.051	0.774	(0.599 to 1.001)	0.051
Subtype	0.429	(0.201 to 0.916)	0.029	0.402	(0.171 to 0.945)	0.037
MRAOS	0.642	(0.505 to 0.816)	<0.001	0.740	(0.532 to 1.029)	0.073
MFQ Total	1.034	(1.010 to 1.059)	0.005	1.042	(1.004 to 1.083)	0.032
2 years
Age	0.661	(0.521 to 0.840)	0.001	0.700	(0.536 to 0.914)	0.009
Weight for height	0.947	(0.909 to 0.986)	0.008	0.961	(0.915 to 1.008)	0.105
EDI-2 Total	1.009	(1.002 to 1.016)	0.018	1.008	(0.995 to 1.020)	0.232

Economic evaluation results

Economic evaluation at 2 years

Data availability

Full economic data for the 2-year follow-up period were available for 135 young people (81%), 47 in the inpatient group, 45 in the specialist outpatient group and 43 in the general CAMHS group. A comparison of baseline characteristics (site, age, gender, BMI and MRAOS) revealed no significant differences between those included in the economic evaluation and those who were missing and there was no difference overall in missing data between the three treatment groups. Length of follow-up varied somewhat (range 99 to 118 weeks); however, there was no significant difference in length of follow-up between the three treatment groups on average (mean 105 weeks in the inpatient and general CAMHS groups and 106 in the specialist group).

Resource use

The mean number of contacts the young people had with all services over the 2-year follow-up period is detailed in Table 23. Service use differed little between the randomised groups except for use of hospital inpatient and outpatient services. The general CAMHS group spent more time in hospital and had a greater number of outpatient attendances on average than the specialist outpatient or inpatient groups and the specialist outpatient group spent the least amount of time in hospital. Exploring hospital contacts over the 1-year, 2-year and 5-year follow-up periods revealed a reduction in the use of hospital services over time: a larger proportion of days were spent in hospital in the first year (inpatient group 64 days, specialist outpatient 35 days, general CAMHS 67 days) than the second year (inpatient group 12 days, specialist outpatient 20 days, general CAMHS 24 days). By 3–5 years, the average number of inpatient days per annum fell further (inpatient group 5 days, specialist outpatient 9 days, general CAMHS 8 days) (see Table 29). When study participants in one of the outpatient groups received inpatient treatment, this generally occurred after assigned treatment had ended. Details of adherence to treatment have been discussed and are given in Tables 12 and 13.

TABLE 23 - Use of resources during the 2-year follow-up period: mean per young person

Service	General CAMHS (n = 43)	Specialist outpatient (n = 45)	Specialist inpatient (n = 47)
	Mean (SD)	Mean (SD)	Mean (SD)
Secondary health services
Inpatient nights	89 (159)	55 (114)	73 (124)
Outpatient appointments	31 (24)	26 (22)	23 (20)
Day patient contacts	1 (5)	1 (7)	4 (12)
Accident and emergency	0 (1)	1 (2)	0 (1)
Community health and social services
General practitioner	6 (8)	7 (9)	7 (9)
Practice nurse	1 (4)	3 (10)	2 (5)
Medication	63%	58%	60%
Dietician	0 (0)	0 (0)	0 (3)
District nurse	0 (0)	0 (2)	0 (0)
Health visitor	0 (0)	0 (0)	0 (1)
Community paediatrician	0 (3)	0 (0)	0 (1)
Community psychiatric nurse	1 (5)	1 (7)	0 (1)
Clinical psychologist	0 (0)	0 (1)	1 (8)
Counsellor	0 (1)	0 (2)	0 (1)
Family therapist	0 (2)	0 (0)	1 (8)
Dentist	0 (0)	0 (1)	0 (0)
School doctor	0 (0)	0 (0)	0 (2)
School nurse	1 (2)	1 (2)	1 (6)
Social worker	0 (1)	1 (4)	1 (2)
Foster care	2 (13)	0 (0)	0 (0)
Eating disorders association	0 (0)	0 (1)	0 (1)
Family therapy	0 (0)	0 (1)	0 (1)
Education
State day school months	12 (10)	10 (9)	11 (9)
Independent day school months	1 (5)	2 (6)	1 (4)
Independent boarding school months	0 (2)	0 (0)	0 (1)
Hospital school months	2 (4)	1 (2)	1 (3)
Home tuition months	1 (4)	1 (3)	0 (1)
School counsellor	0 (0)	1 (7)	1 (7)
Education welfare officer	0 (1)	0 (1)	0 (0)

Although the hospital contacts reported in Table 23 include all medical specialties, the vast majority of contacts were psychiatric (73% of inpatient admissions and 90% of inpatient days) or paediatric (20% of admissions and 10% of inpatient days). Other medical specialties used by the young people (9% of admissions and 0.2% of inpatient days) included gastroenterology, general medicine, haematology, intensive care unit, obstetrics, orthopaedics, plastic surgery and urology.

Time spent by the young people in education was similar across the three groups with evidence of substantial periods out of education in this sample; on average, participants spent a significant proportion of the 2-year follow-up period not in education (approximately 10 out of the 24 months follow-up).

Use of resources by the young person’s primary carer is reported in Table 24. Very few differences between randomised groups are evident.

TABLE 24 - Use of health and community resources by primary carer over 2-year follow-up period: mean per carer

Service	General CAMHS (n = 14)	Specialist outpatient (n = 20)	Specialist inpatient (n = 16)
	Mean	Mean	Mean (SD)
Secondary-care services
Inpatient nights	1 (2)	0 (2)	0 (2)
Outpatient appointments	2 (3)	2 (3)	4 (7)
Day patient attendances	0 (0)	0 (0)	0 (1)
Accident and emergency	0 (0)	0 (1)	0 (0)
Primary-care services
General practitioner	8 (13)	4 (5)	7 (8)
Practice nurse	1 (1)	2 (3)	1 (2)
Counsellor/therapist	1 (4)	4 (15)	5 (18)
Medication (%)	64%	40%	56%

Costs

Mean total costs over the 2-year follow-up are detailed in Table 25. Analysis of covariance demonstrated that there were no statistically significant differences between the three groups. In terms of observed differences, the specialist outpatient group was consistently cheaper than the other two groups and the general CAMHS group was the most expensive of the three. The bootstrapped results differed little from the analyses using the raw data and are therefore not reported here. Hospital costs constitute the greatest proportion of total costs (93% in each group), with relatively few community health and social services being used. In Table 26, the individual service contributions to total costs over the 2-year follow-up are reported. It shows that inpatient and outpatient hospital costs make up 81% and 10% of total costs respectively and that the remaining costs constitute a much smaller proportion of total costs.

TABLE 25 - Total cost per young person over the 2-year follow-up period (£)

Analysis of variance adjusted for site, sex, age at baseline, baseline BMI and baseline MRAOS score.

Includes community social, voluntary and private sector services.

Sector	General CAMHS (n = 43)			Specialist outpatient (n = 45)			Specialist inpatient (n = 47)			ANOVAa
	Mean (SD)	Min	Max	Mean (SD)	Min	Max	Mean (SD)	Min	Max	p-value
Secondary health care	37,746 (62,046)	68	269,236	24,724 (46,231)	103	244,043	32,015 (51,541)	69	280,580	0.456
Primary health care	245 (361)	0	2078	385 (873)	0	4325	380 (640)	4	2773	0.503
Education	2654 (2228)	0	12,093	1595 (1456)	0	6393	2098 (2115)	0	8783	0.088
Other community servicesb	150 (806)	0	5244	35 (104)	0	445	37 (110)	0	513	0.504
Total 2-year cost	40,794 (63,652)	1483	274,838	26,738 (46,809)	462	244,174	34,531 (52,439)	86	282,508	0.426
Total cost per week	386 (600)	14	2603	253 (442)	4	2288	325 (487)	1	2588	0.423

TABLE 26 - Individual service contributions to total costs at 2-year follow-up

Service	% of total costs	Cumulative %
Inpatient	81.34	81.34
Outpatient	10.33	91.67
State day school	3.03	94.70
Hospital school	2.67	97.37
Day patient	0.76	98.13
General practitioner	0.38	98.52
Independent day school	0.37	98.89
Medication	0.28	99.17
Accident and Emergency	0.15	99.32
Community psychiatric nurse	0.12	99.44

Figure 5 illustrates change in costs over time, over the 2-year follow-up. It shows the total cost per participant separated by year and clearly demonstrates that the majority of the costs were incurred in the first year after entry to the study, with much lower costs incurred in the second year.

FIGURE 5.

Total cost per young person by year.

Mean total costs of health services used by the young person’s primary carer are reported in Table 27. Overall the primary carers of the specialist outpatient group cost slightly less than those of the inpatient and general CAMHS groups, but this difference was not statistically significant.

TABLE 27 - Total health and community service costs per primary carer over 2-year follow-up period (£)

Analysis of variance adjusted for site, sex, age at baseline, baseline BMI and baseline MRAOS score.

Service	General CAMHS (n = 14)	Specialist outpatient (n = 20)	Specialist inpatient (n = 16)	ANOVAa
	Mean (SD)	Mean (SD)	Mean (SD)	p-value
Community health services	297 (670)	196 (514)	223 (382)
Hospital services	258 (335)	218 (311)	440 (805)
Medication	152 (424)	77 (113)	87 (252)
Total cost	707 (840)	491 (772)	750 (1199)	0.68

Cost-effectiveness analysis

The cost-effectiveness analysis at the 2-year follow-up point employed the rules of dominance and found that the specialist outpatient treatment (bootstrapped mean cost per patient £26,797; bootstrapped mean MRAOS effect 8.35) dominates the inpatient group (£34,371; 8.26) and the general CAMHS group (£40,520; 8.26) because it is both cheaper and more effective. The cost-effectiveness acceptability curve in Figure 6 illustrates the uncertainty associated with the costs and effects of the three treatments at 2 years. It demonstrates that if decision-makers were willing to pay nothing for a unit increase in MRAOS score, then there would be a 80% chance of specialist outpatient services being the most cost-effective strategy, 16% for inpatient services and only 6% for general CAMHS. The probability of specialist outpatient services being the most cost-effective strategy decreases with increasing levels of willingness to pay for gains in effectiveness. This levels out at around 47%, but remains higher than the other two strategies over the full range of willingness-to-pay values shown, and beyond.

FIGURE 6.

Cost-effectiveness acceptability curve for MRAOS score – three arms.

Figure 6 suggests that the probability of our first hypothesis being true is high, i.e. that specialist outpatient services are more cost-effective than general outpatient services. Figure 7 depicts the cost-effectiveness acceptability curve for the second hypothesis – that outpatient services (specialist combined with general CAMHS) are more cost-effective than inpatient services. It shows that there is a greater probability of outpatient services being more cost-effective than inpatient services for the full range of values of willingness to pay.

FIGURE 7.

Cost-effectiveness acceptability curve for MRAOS score – inpatient versus outpatient.

Sensitivity analyses explored the impact of missing data on the results of the cost-effectiveness analysis. Similar relationships between the three arms of the study were found, with specialist outpatient services having a higher probability of being cost-effective than the other groups over a wide range of willingness-to-pay values, using both last-value-carried-forward and mean imputation techniques. At a zero level of willingness to pay for effectiveness gains, the probability of being the most cost-effective option ranged between 72 and 80% for specialist outpatient services, 13 and 14% for inpatient services and 7 and 16% for general CAMHS. The probability of general CAMHS being the most cost-effective option remains low for all values of willingness to pay. The probability of inpatient services being the most cost-effective option increases as willingness to pay increases, whereas the probability for specialist outpatient services falls. At values of willingness to pay over £100,000, the probability for inpatient services overtakes that for specialist outpatient services but only for the last-value-carried-forward imputation. In all other missing data sensitivity analyses, the specialist outpatient service dominates across the full range of values of willingness to pay.

The cost of education received by study participants was included to explore the additional costs associated with greater disruption as a result of longer admissions to hospital or greater illness severity, such as hospital school attendance or home tuition. However, it is also the case that education may be more expensive because a young person has better attendance (a good outcome). For this reason, we undertook a further sensitivity test, which excluded the cost of education. This analysis left the results of the base-case cost-effectiveness analysis unchanged.

Method

All 215 participants and their parents (randomised and non-randomised) were contacted at 1 year for a full clinical assessment. At this point they were given a satisfaction questionnaire to return anonymously by post. This asked them to rate their prior expectations of any treatment they had received (randomised or not) on a seven-point Likert scale (from very positive, to very negative). It then asked them their subsequent level of satisfaction with each treatment received over the course of the year. Participants were also invited to give free comments about any aspect of the services they had received. Many subjects received further treatment during year 2 of the trial. If this included one of the three treatment options not received in year 1, their views on this were elicited, by way of further quantitative ratings and comments by questionnaire at the 2-year follow-up. The quantitative (Likert scale) ratings were collated and simple frequencies were compared across treatment groups.

The qualitative evaluation comprised an analysis of the free comments from the questionnaire supported by data derived from a subsequent series of focus groups.

The authors were familiar with the eating disorder satisfaction literature but a process for data analysis was chosen that aimed to minimise the effect of any preconceptions. The free comments were analysed with the aim of establishing common satisfaction themes through a series of steps, following the established qualitative methodologies described by Mason. 74 First, the comments were collected and coded according to treatment option and whether by parent or child. Then comments from one of the two sites (n approximately 200) were reviewed separately by the three authors who proposed their own series of themes (open coding). These themes were then extensively discussed between coders, resulting in a consensus and a provisional set of agreed themes.

The printed comments were then reduced to individual elements, coded by whether they were positive or negative about the service in question and collated according to the provisional themes. The comments allocated to each theme were reread and the themes were modified several times until there was agreement on the minimum number that reflected the content of the comments. The rest of the data were then allocated according to these themes (focused coding) with no new themes emerging from these data.

In the second qualitative stage, focus groups for parents and adolescents were arranged in the two main sites to further explore the themes and identify any other important issues that were not highlighted in the questionnaires. Purposive sampling was used to select a varied group of participants, receiving each of the treatments but only a relatively small number (n = 21) were able to take part. Incidental expenses were offered.

A questioning route was developed for the focus groups that included general questions about satisfaction and specific questions related to the themes we had identified from the questionnaires and that allowed time for other themes to be raised by participants, following prescribed conventions. 75

The sessions were audio-taped, transcribed, coded and analysed for thematic content in a similar manner to the questionnaire data. 74 Themes were developed, the materials in the focus group were aggregated and the themes were reviewed and modified several times. Other members of the research team then reviewed the themes and the illustrative quotes to reach a consensus that they could be justified from the transcribed material.

To ascertain the independent validity of the themes, an external researcher was given a structured recoding task to match all 430 comments from the questionnaires and focus groups to a list of 10 themes or identify additional themes not covered.

Results

The questionnaire response rate was 76% (160 out of 215) for adolescents and 71.8% (150 out of 215) for parents. The rate of response by treatment group was proportional to the numbers receiving it, suggesting that there was no response bias by treatment received. As some participants received more than one treatment, the total number giving an opinion of each treatment option exceeded the number of participants in the trial. For the purposes of analysis, the three negative categories and the three positive categories were collapsed for both expectation and satisfaction.

Summary of clinical trial

The TOuCAN trial was successful in recruiting in excess of the required number of cases as calculated by the power estimate. As such, this trial represents the largest RCT of AN carried out to date; successfully recruiting the vast majority of new cases known to CAMHS during the recruitment phase. It is a population-based pragmatic, effectiveness RCT based on the range of NHS treatments available in the north-west of England and probably typical of the rest of the country. One of these treatments (the specialist outpatient programme) was manualised, with fidelity checks; the other two arms represented treatment ‘as usual’ in generic CAMHS and the four regional inpatient units.

Tracing and follow-up were also satisfactory and almost complete to the 2-year time point but less so at 5 years. Reliable and robust outcome measures were used.

Adherence to treatment allocation was less than optimal, reflecting the real world of services and in particular attitudes of patients with AN and their families to treatment. Nevertheless, the data collected and its analysis are adequate to answer the clinical hypotheses:

• Inpatient treatment is not more clinically effective than outpatient treatment.

• Specialist treatment was not found in this study to be more effective than general CAMHS treatment – at least in the short term but it may possibly be in the longer term.

The subanalysis of those allocated to inpatient treatment, examining adherence, suggests poorer outcomes for those actually admitted, even taking into account the baseline levels of measured psychopathology. However, these findings should be treated cautiously given that the two subgroups (adhering and not), may differ on significant but unmeasured variables such as motivation and ability to respond to the assessment interview in the immediate days before admission was available.

The analysis of prognostic indicators reveals that baseline levels of morbidity (chiefly the main outcome measure – MRAOS) and degree of thinness (percentage weight for height) are powerful predictors of service use and medium-term to long-term outcome. Self-reported eating psychopathology at baseline is also a notable predictor of long-term outcome based on the main outcome measure.

Anorexia nervosa is often a chronic disorder in which a number of young people are still ill with the condition at 5-year follow-up. However, it is not primarily a remitting and relapsing disorder, with those who managed to achieve recovery tending to stay well.

Summary of economic analysis

This study represents the first economic evaluation of alternative strategies for the treatment of AN using primary data collected from an RCT.

At 2 years, the specialist outpatient group were the least costly and the general CAMHS group was the most costly, although these results were not statistically significant. These findings were robust to sensitivity analysis of the discount rate and in analyses of missing data. Observed differences in total mean cost per patient were almost entirely the result of differences in the length of time spent in hospital.

The majority of inpatient admissions took place during the first year and there was substantial cross-contamination of groups. For example, although not randomised to psychiatric inpatient services, the general CAMHS group spent almost as much time in hospital as the inpatient group. This finding suggests that general CAMHS were less successful at maintaining the young people in the community than the specialist outpatient services.

With the exception of CAMHS, participants used very few community health and social services. The number of months in education was similar across the groups on average, though the relatively low mean number of months in this adolescent population highlighted the significant proportion of time participants spent out of education, presumably as a result of their illness.

The annual service costs of caring for this group of young people, £17,000, are substantial and much higher than the cost of conditions generally treated in the community – for example, conduct disorder with annual service cost estimates varying between £1300 and £3200. 58,72 However, the annual cost is similar to the cost of a cohort of young people with mental health problems that led to them being treated in child and adolescent psychiatric inpatient wards, estimated to be £24,000 per admission. 76 The slightly higher costs in this case were the result of longer mean lengths of stay, on average.

The results of the cost-effectiveness analysis reveal that specialist outpatient services were the dominant treatment option in terms of incremental cost-effectiveness, as they were more effective and less costly. The cost-effectiveness acceptability curves, which consider associated uncertainty, support this finding. In terms of our hypotheses, the data suggest that specialist outpatient services have a higher probability of being cost-effective than general CAMHS and that outpatient services (specialist combined with general) have a higher probability of being cost-effective than inpatient services.

By the 5-year follow-up, hospital-use information was available for less than half of the randomised cases, and the skewed nature of the data (because of a small number of young people with lengthy hospital or day-case admissions) makes it difficult to reach conclusions on differences in resource use and costs. Some clear findings do emerge however. First, the trend in reductions in hospital use between years 1 and 2 was maintained over the longer term with, on average, much lower use of hospital services by 5 years follow-up. Second, there were no differences in average total cost per young person between randomised groups.

Univariate regression analysis at 5-years demonstrated that more severe cases of anorexia nervosa at baseline, including those with lower percentage weight for height and lower MRAOS scores (poorer health), cost significantly more in terms of hospital costs over the 5-year follow-up. In addition, those with more severe mental health problems, as measured by the MFQ and the HoNOSCA-CR, cost significantly more in terms of hospital costs over the 5-year follow-up. However, when these variables were included in a multiple regression analysis, only weight for height remained significant, suggesting that thinness at baseline was the most important factor predicting high costs in terms of hospital services over 5 years.

Summary of satisfaction study

This study provided a wealth of information from both users and carers in relation to their experience of the range of treatment approaches.

Overall, levels of satisfaction with services were good with young people being twice as likely to express positive as negative views of their treatment. Parents were much more satisfied with about five times as many expressing positive as negative views of treatment. Parents were consistently more satisfied than young people with each treatment, but both parents and young people were more satisfied with specialist than general treatments. The satisfaction of both young people and their parents was largely based on their confidence in ‘expertise’ and forging a good relationship with an individual therapist working on either an inpatient or an outpatient basis.

Discussion

This pragmatic treatment trial has attempted to address the issues posed by the brief concerning the merits of different models of care for adolescent AN. Specifically, little was previously known of the relative clinical effectiveness and cost-effectiveness of different service settings or young people’s and their parents’ satisfaction with these. 11 The brief was an important one because of the extremely high cost of inpatient care,35,61 when stays commonly last several months and when AN makes a major demand on adolescent inpatient services. 5 The facility to offer long-term psychiatric (as opposed to medical) treatment in the UK has often been highly valued, clinical intuition suggesting that more intensive treatments should be more effective than briefer, non-specialist treatment for a condition that is often chronic and has a high morbidity and mortality.

Previous cohort and treatment studies28,37,41 have raised questions about the value of inpatient care, but without a randomised allocation to inpatient care it has been difficult to evaluate the benefits of admission over and above outpatient management; although the one systematic review concluded that outpatient treatment in a specialist eating disorder service was as effective as inpatient treatment in those not so severely ill as to warrant emergency admission. Furthermore, these reviewers estimated the costs of outpatient treatment to be approximately one-tenth the cost of inpatient treatment. 27

Not surprisingly, given the ambivalence of young people with AN to treatment and the large personal and family investment required of those admitted to inpatient care, adherence to this arm of the trial was unavoidably less than optimal. In addition, given the often chronic nature of the condition, it was not possible to keep patients treatment-free between the treatment and follow-up phases. It might be argued that a 6-month follow-up assessment point would have been useful to assess the trial interventions before the picture became blurred by subsequent treatment. However, we deliberately avoided doing this as recommendations in this field11 suggest 2 years as a minimum useful follow-up point and because it is well known that inpatient gains are often short-lived (for example in the St George’s and Maudsley trials28,41) and so such an assessment point would be likely to favour this treatment arm.

Nevertheless, this trial has reached some important conclusions, particularly given the recruitment design, which was highly inclusive, population-based and used readily available CAMHS. This study is much larger than those reported in the literature to date and includes around four-fifths of incident cases known to child and adolescent mental health services in the north-west of England over a 3-year period. We achieved a high follow-up rate with demonstrably reliable outcome measures.

The findings challenge a number of notions about care for this disorder. In particular, psychiatric inpatient treatment does not confer advantages over outpatient care, and is associated with a lower probability of being cost-effective than the combined outpatient groups. Although adherence to inpatient care was only 50%, the subanalysis reveals that rather than the outcome of this arm being adversely affected by a lack of adherence, in fact, the overall (intention-to-treat) outcomes are improved by the better outcomes of those declining admission once offered it. The subanalysis of those accepting or declining admission within the inpatient arm should, however, be interpreted with caution. It may be that the decision to accept randomised admission is based on a number of negative prognostic variables, rather than it reflecting on the inpatient treatment itself. Based on the predictive model for admission developed among patients not admitted, one can see that those adhering to admission had a higher probability of admission based on baseline characteristics. Possibly some unmeasured variables such as motivation or family resources may have accounted for the difference in response.

This finding does not deny the necessity of emergency medical management of physical complications in an inpatient setting, which may on occasions be life-saving, but our results do suggest that inpatient management is rarely associated with comprehensive recovery, as opposed to improvement or stability within the condition.

The finding that specialist care offers few advantages requires clarification. In some respects the findings mirror the results from the New Zealand trial,77 in which an adult (and probably less severely unwell) series did as well with non-specific supportive clinical management as with two specialist psychological therapies. As with this trial, it is important not to underestimate the quality of the ‘control’ or generic intervention. General CAMHS (as opposed to adult Community Mental Health Teams, for example) commonly offer psychological therapies (often based on CBT) and family-based treatments in the context of a developmental perspective – an approach which suits this condition well. However, the greater success of specialist outpatient services at maintaining young people in the community resulted in a poorer performance in terms of cost-effectiveness for general CAMHS. This relative cost-effectiveness of specialist care may be the result of the inexperience of managing AN in the CAMHS teams and the resulting anxiety which may have led to the more frequent hospital admissions and costs of this treatment. This anxiety may in turn have transmitted itself to the families involved, leading to lower levels of satisfaction.

It is also of note that the specialist outpatient arm was the only manualised treatment and also incorporated fidelity checks. This may have added to its effectiveness and these components are essential in comparing findings across different studies.

Our study suggested that there was a reasonably high level of satisfaction for each of the treatment groups in this trial, by parent and, to a lesser extent, patient perspective. The overall response rate (over 72%) would appear good for a satisfaction measure, but we are unable to say whether non-responders would have been less satisfied over all, or with one particular treatment option. As in a Norwegian study,78 this was in spite of the clinical outcomes. When expectations of a service are greater than perceived performance, then quality will be judged as less satisfactory and dissatisfaction will be high. Although definitions of satisfaction vary, satisfaction has been defined as being about ‘the appraisal of the extent to which the care provided has met the individual’s expectations and preferences’. 79 In our study, parental expectations were very high, rendering them liable to dissatisfaction when the experience was less than anticipated.

The literature often reveals negative experiences of inpatient treatment. A postal survey of members of the Eating Disorders Association78 revealed mixed experiences, with slightly more respondents feeling this made the situation worse than found it very helpful. These findings were largely replicated in a Norwegian survey that showed patients were relatively satisfied with outpatient individual and group therapies (and to a lesser extent with family therapy) and dissatisfied with inpatient treatment. 81 This survey showed that patients particularly valued therapist expertise, results duplicated in a survey of 300 patients from the Netherlands. 80

The most reported theme in our series – the importance of a relationship with an individual professional – replicates findings from previous research in the eating disorder field and within mental health more generally. Good generic psychotherapeutic skills are seen as very important by service users. All three treatment modalities in the study generally aimed to provide these and there was no perception that therapy was overly focused on physical aspects.

General CAMHS compared unfavourably with specialist outpatient and inpatient services, mainly because of a perceived lack of expertise with eating disorders. It may be that when parents and adolescents are accessing specialist services, they feel reassured that they are in the right hands because of the ‘specialist’ status even if they are not making significant clinical progress. This view was borne out by the quantitative data, which suggested that adolescents had lower expectations of CAMHS, than other treatments, though strikingly 86% of parents had positive expectations of CAMHS treatment. During the TOuCAN study, a survey of the local CAMHS teams found that the average number of AN presentations to CAMHS was around two or three cases a year. It may well be that generic clinicians do not become familiar with working with what can be a particularly demanding condition and at particularly worrying stages of the treatment; professionals without experience of eating disorders may therefore find it harder to maintain the positive aspects of their therapeutic relationship. Experienced specialists working with colleagues with similar expertise may be more able to maintain warmth, hope and positivity in the face of uncertain outcomes and the chronic nature of the condition, and also possibly avoid the hospital admissions which drive up costs. Greater patient flows also enable specialist services to incorporate dietetics and creative therapies into their treatment programmes.

It is encouraging that unlike previous reports, we did not find that families reported feeling blamed by services for the condition of their daughter or son. In fact they greatly valued the support that they received and their involvement in treatment. A strong message was given in the focus groups about the impact of eating disorders on siblings. This should encourage services to continue to offer parental and family therapies in keeping with NICE recommendations.

Limitations of the trial

It could be argued that the inpatient services in the study were not truly specialised because they were not exclusive eating disorder facilities. However, all four units had extensive experience and tradition of treating such cases. Indeed 17 cases entered other (often exclusive) specialist inpatient services in the follow-up period of the study and nevertheless, had (generally) poor outcomes at 2 years.

The present study was devised before the more recent positive outcomes of family-based treatment81 were published and it is of note that our findings suggest poorer outcomes. We had been impressed by the preliminary outcomes of CBT-Enhanced16 in addressing the core psychopathology of eating and weight concerns, and questioned the power of family-based treatment to address these as opposed to behavioural aspects of the condition.

The outcome of our individual CBT was poorer than reported for family-based treatment – a direct comparison is required on a similar population to clarify this further.

In the cost-effectiveness analysis, despite substantial observed differences in costs between groups, the differences did not reach statistical significance at 2 years. This may be because of inadequate sample sizes for the economic evaluation because sample size calculations were based on the primary outcome measure, the MRAOS. Calculations on the basis of cost or cost-effectiveness were not feasible at the design stage because of the lack of any relevant published cost data, but it is possible that a sample calculated in this way may have required a much larger sample. Although acknowledging this limitation, the use of a decision-making approach to the economic evaluation provides probabilistic evidence of the cost-effectiveness of the alternative treatment strategies, given the data currently available. Larger trials may be considered in the future, but this must be balanced against the cost of additional research in a disease area where low prevalence rates necessitate large and resource intensive multicentre evaluation.

Analysis of patients excluded because of missing economic data at both 2 and 5 years did not suggest any bias; patients included in the economic evaluation did not differ significantly from those excluded and there was no evidence to suggest any bias in missing data between the three treatment groups. On the whole, exploration of missing data in sensitivity analysis supported the results of the main analysis.

This study was able to demonstrate the value of economic evidence as a decision-making tool in situations where clinical differences between treatments are minimal. However, the value of the results presented is more limited in a broader decision-making context because of the lack of a generic, preference-based measure of outcome. NICE guidelines, for example, require evidence of cost-effectiveness (to be presented in terms of cost per quality-adjusted life-year) to allow comparison across diverse disease areas to support the allocation of scarce societal health and personal social services resources. 65 Future studies should consider the inclusion of such measures so as to place services for adolescents with AN within this broader decision-making context.

Implications for health care

For moderately to severely ill adolescents with AN, outpatient services delivered by experienced, expert professionals, supported by medical management of physical complications as required, offer the most cost-effective treatments. Lengthy psychiatric inpatient treatment does little to add to positive outcomes and is cost-ineffective. Treatment in specialist services, with experience and expertise in managing the condition, is to be preferred because of its cost-effectiveness and higher levels of both young people’s and carer’s satisfaction. Where young people with AN are managed in community CAMHS, a consultation and advice link with a specialist service may enable the CAMHS to contain anxiety and reduce unnecessary hospital admissions, thereby leading to greater user satisfaction. This needs further investigation.

The findings are broadly consistent with the NICE guidelines on the treatment of AN. Although physical risk should not be underestimated and may require urgent and active intervention, this trial does not lend support to the advantages of managing this within a psychiatric service.

Recommendations for future research

Further research is recommended in the following areas.

Contributions of authors

Simon G. Gowers was the principal investigator and designed the study and was lead author of the report. Andrew F. Clark led the research at the Manchester site and contributed to writing and editing the report. Chris Roberts, lead statistician, helped in the statistical design, analysis and report writing and editing. Sarah Byford and Barbara Barrett were responsible for health economic design, analysis, report writing and editing. Alison Griffiths, Vanessa Edwards, Claudine Bryan and Nicola Smethurst were project trial managers and contributed to clinical support, data management, tracing and report editing. Laura Rowlands, a project trial manager, helped with clinical support, data management, tracing, the satisfaction study and the report editing and Peter Roots lead the satisfaction study and contributed to editing the report.

Publications

Gowers SG, Clark A, Roberts C, Griffiths A, Edwards V, Bryan C, et al. Clinical effectiveness of treatment for anorexia nervosa in adolescents – Randomised controlled trial. Br J Psychiatry 2007:191;427–35.

Byford S, Barrett B, Roberts C, Clark A, Edwards V, Smethurst N, et al. Economic evaluation of a randomised controlled trial for anorexia nervosa in adolescents. Br J Psychiatry 2007:191;436–40.

Roots P, Rowlands L, Gowers S. User satisfaction with services in a randomized controlled trial of adolescent anorexia nervosa. Eur Eat Disord Rev 2009:17;331–37.

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.

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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, Reimsma 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, 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.