Trajectories of depression and anxiety symptom severity during psychological therapy for common mental health problems.

BACKGROUND: There is substantial variation in patient symptoms following psychological therapy for depression and anxiety. However, reliance on endpoint outcomes ignores additional interindividual variation during therapy. Knowing a patient's likely symptom trajectories could guide clinical decisions. We aimed to identify latent classes of patients with similar symptom trajectories over the course of psychological therapy and explore associations between baseline variables and trajectory class. METHODS: Patients received high-intensity psychological treatment for common mental health problems at National Health Service Improving Access to Psychological Therapies services in South London (N = 16 258). To identify trajectories, we performed growth mixture modelling of depression and anxiety symptoms over 11 sessions. We then ran multinomial regressions to identify baseline variables associated with trajectory class membership. RESULTS: Trajectories of depression and anxiety symptoms were highly similar and best modelled by four classes. Three classes started with moderate-severe symptoms and showed (1) no change, (2) gradual improvement, and (3) fast improvement. A final class (4) showed initially mild symptoms and minimal improvement. Within the moderate-severe baseline symptom classes, patients in the two showing improvement as opposed to no change tended not to be prescribed psychotropic medication or report a disability and were in employment. Patients showing fast improvement additionally reported lower baseline functional impairment on average. CONCLUSIONS: Multiple trajectory classes of depression and anxiety symptoms were associated with baseline characteristics. Identifying the most likely trajectory for a patient at the start of treatment could inform decisions about the suitability and continuation of therapy, ultimately improving patient outcomes.

Management of fraudulent participants in online research: Practical recommendations from a randomized controlled feasibility trial.

OBJECTIVE: Fraudulent participation is an escalating concern for online clinical trials and research studies and can have a significant negative impact on findings. We aim to shed light on the risk and to provide practical recommendations for detecting and managing such instances. METHODS: The FREED-Mobile (FREED-M) study is an online, randomized controlled feasibility trial to assess a digital early intervention for young people (aged 16-25) in England or Wales with eating problems. The trial involved baseline (week 0), post-intervention (week 4), and follow-up (week 12) surveys, alongside weekly modules provided over 4 weeks on the study website. Study completers were compensated with £20 shopping vouchers. Despite the complexity of the trial design, two instances of fraudulent sign-ups occurred in January and March 2023. To counter this, we developed a "fraudulent participants protocol" following internal investigations and discussions with collaborators. RESULTS: The implementation of prevention measures such as reCAPTCHA updates, IP address review, and changes in reimbursement effectively halted further fraudulent sign-ups. Our protocol facilitated the systematic identification and withdrawal of suspected or clear fraudsters and was demonstrably robust at distinguishing between fraudsters and genuine responders. DISCUSSION: All remote, online trials or studies are at risk of fraudulent participation. Drawing from our experience and existing literature, we offer practical recommendations for researchers considering online recruitment and data collection. Vigilance and the integration of deterrents, and data quality checks into the study design from the outset are advised to safeguard research integrity. PUBLIC SIGNIFICANCE: Fraudulent participation in digital research can have asignificant impact on research findings, potentially leading to biased resultsand misinformed decisions. We developed an effective protocol for theprevention, identification, and management of fraudulent participants. Bysharing our insights and recommendations, we hope to raise awareness of thisissue and provide other researchers with the knowledge and strategies necessaryto safeguard research integrity moving forward.

Childhood gender-typed behaviour, sexual orientation, childhood abuse and post-traumatic stress disorder: a prospective birth-cohort study.

ALSPAC birth-cohort data were analysed to assess prospective associations between childhood gender nonconformity (CGN), childhood/adolescent abuse, and adulthood PTSD symptoms. Structural equation models assessed whether abuse mediated the relationship between CGN and PTSD. Sex and sexual orientation differences were investigated. For females, higher parent-rated CGN at 30, 42 and 57-months was associated with mother-reported abuse, self-reported physical/psychological abuse, and/or self-reported sexual abuse. Higher CGN at 30-months was associated with more PTSD symptoms at 23 years. Self-rated CGN in males and females, and parent-rated CGN in males, were not associated with abuse or PTSD. Sexual minority identification was associated with higher CGN and abuse and for females, PTSD symptoms. In females, the relationship between greater CGN at 30-months and PTSD symptoms was separately mediated by each abuse variable. Self-reported sexual abuse was no longer a significant mediator after sexual orientation adjustment. Self-reported physical/psychological abuse significantly mediated the association alone when it was entered together with mother-reported abuse, even after sexual orientation adjustment. In conclusion, childhood gender nonconformity in females may increase the risk for adult PTSD symptoms, possibly mediated by childhood abuse. In females, mediation of the relationship between CGN and PTSD by sexual abuse may be particularly relevant for sexual minority individuals.

Mediators of the Disparities in Depression Between Sexual Minority and Heterosexual Individuals: A Systematic Review.

Evidence suggests that sexual minorities (e.g., those identifying as lesbian, gay, or bisexual) experience increased rates of depression compared to heterosexual individuals. Minority stress theory suggests that this disparity is due to stigma experienced by sexual minorities. Stigma processes are proposed to contribute to reduced coping/support resources and increased vulnerability processes for mental health problems. This review provided a systematic examination of research assessing the evidence for mediating factors that help explain such disparities. A literature search was conducted using the databases PubMed, PsycINFO, and Web of Science. The review included 40 identified studies that examined mediators of sexual minority status and depressive outcomes using a between-group design (i.e., heterosexual versus sexual minority participants). Studies of adolescents and adult samples were both included. The most common findings were consistent with the suggestion that stressors such as victimization, harassment, abuse, and increased stress, as well as lower social and family support, may contribute to differing depression rates in sexual minority compared to heterosexual individuals. Differences in psychological processes such as self-esteem and rumination may also play a role but have had insufficient research attention so far. However, caution is needed because many papers had important methodological shortcomings such as the use of cross-sectional designs, inferior statistical analyses for mediation, or measures that had not been properly validated. Although firm conclusions cannot be drawn, the current evidence base highlights many factors potentially suitable for further exploration in high-quality longitudinal research or randomized studies intervening with the potential mediators.

Childhood gender-typed behavior and emotional or peer problems: a prospective birth-cohort study.

BACKGROUND: Retrospective and cross-sectional studies often report associations between childhood gender nonconformity and greater emotional and peer difficulties. This study used the ALSPAC birth cohort to investigate relationships between childhood gender-typed behavior and peer and emotional problems throughout childhood and adolescence. METHODS: A total of 11,192 participants had at least one measure of parent-rated gender-typed behavior in infancy; 7,049 participants had a measure of child-rated gender-typed behavior at 8.5 years. Separate linear mixed regression models were fitted to assess whether parent-rated and child-rated gender-typed behaviors were associated with emotional and peer problems across childhood and adolescence (6-16 years old). The effect of adding covariates (self-esteem, abuse, bullying, feeling accepted by peers, and feeling different) on these relationships was assessed. RESULTS: For boys, more gender-nonconforming behavior was associated with greater subsequent emotional and peer problems in childhood and adolescence. Adjusting for self-esteem, relational bullying victimization, feeling different, or feeling accepted by peers reduced some of these associations. In contrast, for girls, more gender-nonconforming behavior was associated with fewer emotional problems in childhood and adolescence. In girls, self-reported gender-nonconforming behavior was also associated with fewer parent-rated peer problems but parent-rated gender-nonconforming behavior was associated with more parent-rated peer problems; this latter association was partly explained by self-esteem, bullying, and abuse victimization. These associations were statistically significant but small. CONCLUSIONS: Overall, more female-typical behaviors were generally associated with greater subsequent emotional and peer problems, for both boys and girls. Future studies should investigate factors that reduced these associations, as well as potential negative effects of female-typical behaviors or advantages of male-typical ones. As this was a 14-year longitudinal study, the relationships between gender-role behaviors and emotional/peer problems warrant further research despite the small association sizes.

Psychometric Properties and Factor Structure of a Long and Shortened Version of the Cognitive and Behavioural Responses Questionnaire.

OBJECTIVE: Symptoms of chronic fatigue syndrome (CFS) can be perpetuated by cognitive and behavioral responses to the illness. We aimed to determine the factor structure, reliability, and validity of the 40-item Cognitive and Behavioural Responses Questionnaire (CBRQ) using data gathered from CFS patients. We also propose a short-version CBRQ for greater clinical utility. METHODS: The psychometric analysis was performed on data sets drawn from two sources: a clinical service for CFS patients (n = 576) and the PACE randomized controlled trial of CFS treatments (n = 640). An exploratory factor analysis was conducted on the clinical data set and a confirmatory factor analysis was performed on the randomized controlled trial data set. Using these results, a short version of the CBRQ was proposed. Reliability, metric invariance across age and sex, and construct validity were assessed. RESULTS: The exploratory factor analysis (relative χ = 2.52, root mean square error of approximation = 0.051, comparative fit index = 0.964, Taylor-Lewis Index = 0.942) and confirmatory factor analysis (relative χ = 4.029, root mean square error of approximation = 0.069, comparative fit index = 0.901, Taylor-Lewis Index = 0.892) revealed that eight-factor models fitted the data well. Satisfactory Cronbach's α values were obtained for the final subscales (≥0.76). The shortened CBRQ was obtained by removing items that cross-loaded onto other factors and/or were the lowest loading items in each factor. The shortened CBRQ contained 18 items that had high factor loadings, good face validity, and reliability (Cronbach's α = 0.67-0.88). CONCLUSIONS: The CBRQs, long and short versions, are reliable and valid scales for measuring cognitive and behavioral responses of patients with CFS. Further research is needed to examine the utility of the CBRQ in other long-term conditions.

One-day cognitive-behavioural therapy self-confidence workshops for people with depression: randomised controlled trial.

BACKGROUND: Despite its high prevalence, help-seeking for depression is low. AIMS: To assess the effectiveness and cost-effectiveness of 1-day cognitive-behavioural therapy (CBT) self-confidence workshops in reducing depression. Anxiety, self-esteem, prognostic indicators as well as access were also assessed. METHOD: An open randomised controlled trial (RCT) waiting list control design with 12-week follow-up was used (trial registration: ISRCTN26634837). A total of 459 adult participants with depression (Beck Depression Inventory (BDI) scores of ≥ 14) self-referred and 382 participants (83%) were followed up. RESULTS: At follow-up, experimental and control participants differed significantly on the BDI, with an effect size of 0.55. Anxiety and self-esteem also differed. Of those who participated, 25% were GP non-consulters and 32% were from Black and minority ethnic groups. Women benefited more than men on depression scores. The intervention has a 90% chance of being considered cost-effective if a depression-free day is valued at £14. CONCLUSIONS: Self-confidence workshops appear promising in terms of clinical effectiveness, cost-effectiveness and access by difficult-to-engage groups.

Factors associated with anxiety disorder comorbidity.

BACKGROUND: Anxiety and depressive disorders often co-occur and the order of their emergence may be associated with different clinical outcomes. However, minimal research has been conducted on anxiety-anxiety comorbidity. This study examined factors associated with anxiety comorbidity and anxiety-MDD temporal sequence. METHODS: Online, self-report data were collected from the UK-based GLAD and COPING NBR cohorts (N = 38,775). Logistic regression analyses compared differences in sociodemographic, trauma, and clinical factors between single anxiety, anxiety-anxiety comorbidity, anxiety-MDD (major depressive disorder) comorbidity, and MDD-only. Additionally, anxiety-first and MDD-first anxiety-MDD were compared. Differences in familial risk were assessed in those participants with self-reported family history or genotype data. RESULTS: Anxiety-anxiety and anxiety-MDD had higher rates of self-reported anxiety or depressive disorder diagnoses, younger age of onset, and higher recurrence than single anxiety. Anxiety-MDD displayed greater clinical severity/complexity than MDD only. Anxiety-anxiety had more severe current anxiety symptoms, less severe current depressive symptoms, and reduced likelihood of self-reporting an anxiety/depressive disorder diagnosis than anxiety-MDD. Anxiety-first anxiety-MDD had a younger age of onset, more severe anxiety symptoms, and less likelihood of self-reporting a diagnosis than MDD-first. Minimal differences in familial risk were found. LIMITATIONS: Self-report, retrospective measures may introduce recall bias. The familial risk analyses were likely underpowered. CONCLUSIONS: Anxiety-anxiety comorbidity displayed a similarly severe and complex profile of symptoms as anxiety-MDD but distinct features. For anxiety-MDD, first-onset anxiety had an earlier age of onset and greater severity than MDD-first. Anxiety disorders and comorbidity warrant further investigation and attention in research and practice.

Comparison of symptom-based versus self-reported diagnostic measures of anxiety and depression disorders in the GLAD and COPING cohorts.

BACKGROUND: Understanding and improving outcomes for people with anxiety or depression often requires large sample sizes. To increase participation and reduce costs, such research is typically unable to utilise "gold-standard" methods to ascertain diagnoses, instead relying on remote, self-report measures. AIMS: Assess the comparability of remote diagnostic methods for anxiety and depression disorders commonly used in research. METHOD: Participants from the UK-based GLAD and COPING NBR cohorts (N = 58,400) completed an online questionnaire between 2018 and 2020. Responses to detailed symptom reports were compared to DSM-5 criteria to generate symptom-based diagnoses of major depressive disorder (MDD), generalised anxiety disorder (GAD), specific phobia, social anxiety disorder, panic disorder, and agoraphobia. Participants also self-reported any prior diagnoses from health professionals, termed self-reported diagnoses. "Any anxiety" included participants with at least one anxiety disorder. Agreement was assessed by calculating accuracy, Cohen's kappa, McNemar's chi-squared, sensitivity, and specificity. RESULTS: Agreement between diagnoses was moderate for MDD, any anxiety, and GAD, but varied by cohort. Agreement was slight to fair for the phobic disorders. Many participants with self-reported GAD did not receive a symptom-based diagnosis. In contrast, symptom-based diagnoses of the phobic disorders were more common than self-reported diagnoses. CONCLUSIONS: Agreement for MDD, any anxiety, and GAD was higher for cases in the case-enriched GLAD cohort and for controls in the general population COPING NBR cohort. For anxiety disorders, self-reported diagnoses classified most participants as having GAD, whereas symptom-based diagnoses distributed participants more evenly across the anxiety disorders. Further validation against gold standard measures is required.

A review of health utilities using the EQ-5D in studies of cardiovascular disease.

BACKGROUND: The EQ-5D has been extensively used to assess patient utility in trials of new treatments within the cardiovascular field. The aims of this study were to review evidence of the validity and reliability of the EQ-5D, and to summarise utility scores based on the use of the EQ-5D in clinical trials and in studies of patients with cardiovascular disease. METHODS: A structured literature search was conducted using keywords related to cardiovascular disease and EQ-5D. Original research studies of patients with cardiovascular disease that reported EQ-5D results and its measurement properties were included. RESULTS: Of 147 identified papers, 66 met the selection criteria, with 10 studies reporting evidence on validity or reliability and 60 reporting EQ-5D responses (VAS or self-classification). Mean EQ-5D index-based scores ranged from 0.24 (SD 0.39) to 0.90 (SD 0.16), while VAS scores ranged from 37 (SD 21) to 89 (no SD reported). Stratification of EQ-5D index scores by disease severity revealed that scores decreased from a mean of 0.78 (SD 0.18) to 0.51 (SD 0.21) for mild to severe disease in heart failure patients and from 0.80 (SD 0.05) to 0.45 (SD 0.22) for mild to severe disease in angina patients. CONCLUSIONS: The published evidence generally supports the validity and reliability of the EQ-5D as an outcome measure within the cardiovascular area. This review provides utility estimates across a range of cardiovascular subgroups and treatments that may be useful for future modelling of utilities and QALYs in economic evaluations within the cardiovascular area.

Mapping of the EQ-5D index from clinical outcome measures and demographic variables in patients with coronary heart disease.

BACKGROUND: The EuroQoL 5D (EQ-5D) is a questionnaire that provides a measure of utility for cost-effectiveness analysis. The EQ-5D has been widely used in many patient groups, including those with coronary heart disease. Studies often require patients to complete many questionnaires and the EQ-5D may not be gathered. This study aimed to assess whether demographic and clinical outcome variables, including scores from a disease specific measure, the Seattle Angina Questionnaire (SAQ), could be used to predict, or map, the EQ-5D index value where it is not available. METHODS: Patient-level data from 5 studies of cardiac interventions were used. The data were split into two groups - approximately 60% of the data were used as an estimation dataset for building models, and 40% were used as a validation dataset. Forward ordinary least squares linear regression methods and measures of prediction error were used to build a model to map to the EQ-5D index. Age, sex, a proxy measure of disease stage, Canadian Cardiovascular Society (CCS) angina severity class, treadmill exercise time (ETT) and scales of the SAQ were examined. RESULTS: The exertional capacity (ECS), disease perception (DPS) and anginal frequency scales (AFS) of the SAQ were the strongest predictors of the EQ-5D index and gave the smallest root mean square errors. A final model was chosen with age, gender, disease stage and the ECS, DPS and AFS scales of the SAQ. ETT and CCS did not improve prediction in the presence of the SAQ scales. Bland-Altman agreement between predicted and observed EQ-5D index values was reasonable for values greater than 0.4, but below this level predicted values were higher than observed. The 95% limits of agreement were wide (-0.34, 0.33). CONCLUSIONS: Mapping of the EQ-5D index in cardiac patients from demographics and commonly measured cardiac outcome variables is possible; however, prediction for values of the EQ-5D index below 0.4 was not accurate. The newly designed 5-level version of the EQ-5D with its increased ability to discriminate health states may improve prediction of EQ-5D index values.

Relationship between the EQ-5D index and measures of clinical outcomes in selected studies of cardiovascular interventions.

BACKGROUND: The EuroQoL 5D (EQ-5D) has been widely used in studies of cardiac disease, but its measurement properties in this group are not well established. The study aimed to quantify the relationship between measures commonly used in studies of cardiac disease and the EQ-5D index across different levels of disease severity. METHODS: Patient-level data from 7 studies of cardiac interventions were used, which included randomised trials and observational studies. Relationships between the EQ-5D index and commonly used cardiac measures, Canadian Cardiovascular Society (CCS) angina severity class, treadmill exercise time (ETT) and scales of the Seattle Angina Questionnaire (SAQ) were examined. Mixed effects linear regression was used to assess these relationships, with the EQ-5D index as the response. RESULTS: Study sample sizes ranged from 68 to 2419. Mean baseline EQ-5D index ranged from 0.77 in patients at diagnosis (95% CI 0.75, 0.78) to 0.43 in patients with advanced disease (95% CI 0.39, 0.48) and differed significantly across studies (p < 0.001). There was evidence of a ceiling effect in patients at diagnosis. The minimum clinically important difference of a one minute increase in ETT was associated with a 0.019 (95% CI 0.014, 0.025) increase in EQ-5D index. One class increase in CCS was associated with a 0.11 (95% CI 0.09, 0.13) decrease in EQ-5D index. A 10 unit increase in SAQ scales was associated with increases between 0.04 and 0.07 in EQ-5D index (95% CIs 0.03, 0.05 and 0.05, 0.08). Tests of heterogeneity indicated the EQ-5D-covariate relationships were consistent across levels of disease severity for ETT and the treatment satisfaction scale of the SAQ, but heterogeneous for age, gender, CCS angina class and other scales of the SAQ. CONCLUSION: The EQ-5D index varies with coronary disease severity. The relationship between the EQ-5D index and an outcome measure used in cardiac intervention studies, ETT, was consistent across disease severity levels, but the relationship between demographic variables, CCS angina class and most of the SAQ scales and the EQ-5D index was heterogeneous for patients with different levels of coronary disease. Differences in the EQ-5D index associated with clinically important differences in cardiac measures can be quantified and vary between three important examples - angina class, ETT and SAQ.

The Genetic Links to Anxiety and Depression (GLAD) Study: Online recruitment into the largest recontactable study of depression and anxiety.

BACKGROUND: Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research. METHODS: The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact. RESULTS: Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants' questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages. DISCUSSION: This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression.

Tutorial: The practical application of longitudinal structural equation mediation models in clinical trials.

The study of mediation of treatment effects, or how treatments work, is important to understanding and improving psychological and behavioral treatments, but applications often focus on mediators and outcomes measured at a single time point. Such cross-sectional analyses do not respect the implied temporal ordering that mediation suggests. Clinical trials of treatments often provide repeated measures of outcomes and, increasingly, of mediators as well. Repeated measurements allow the application of various types of longitudinal structural equation mediation models. These provide flexibility in modeling, including the ability to incorporate some types of measurement error and unmeasured confounding that can strengthen the robustness of findings. The usual approach is to identify the most theoretically plausible model and apply that model. In the absence of clear theory, we put forward the option of fitting a few theoretically plausible models, providing a type of sensitivity analysis for the mediation hypothesis. In this tutorial, we outline how to fit several longitudinal mediation models, including simplex, latent growth and latent change models. This will allow readers to learn about one type of model that is of interest, or about several alternative models, so that they can take this sensitivity approach. We use the Pacing, Graded Activity, and Cognitive Behavioral Therapy: A Randomized Evaluation (PACE) trial of rehabilitative treatments for chronic fatigue syndrome (ISRCTN 54285094) as a motivating example and describe how to fit and interpret various longitudinal mediation models using simulated data similar to those in the PACE trial. The simulated data set and Mplus code and output are provided. (PsycINFO Database Record

Delayed re-exploration for bleeding after coronary artery bypass surgery results in adverse outcomes.

OBJECTIVE: We aimed to identify the impact of re-exploration for bleeding after coronary artery bypass grafting (CABG) and the effect of time delay, re-exploration within 12h (<12h) versus 12h or later (>or=12h). METHODS: Analyses of prospective clinical data on 3220 consecutive patients who underwent CABG between 2003 and 2005 were performed. Pearson chi(2) tests, Fisher's exact tests, Student's t-tests, Mann-Whitney U tests, or univariate logistic regression analysis were used to assess the effects of pre-operative and operative characteristics on re-exploration, and the effects of re-exploration and time delay on adverse outcomes. Predictors of re-exploration and its effect on adverse outcomes were further evaluated using multiple logistic regression analysis. RESULTS: One hundred ninety-one patients (5.9%) underwent re-exploration for bleeding. Re-explored patients as a group in comparison to the non-re-explored group had increased postoperative blood loss, transfusion requirements, duration of mechanical ventilation, ICU stay, intra-aortic balloon pump (IABP) and haemofiltration support, and mortality (all p<0.001). One hundred fifty-seven (82%) of the 191 patients were re-explored <12h. The group of patients who were re-explored <12h in comparison to >or=12h group had shorter ICU stay (median 3 vs 8.5 days; p<0.001), less IABP support (22.3 vs 44.1%; p=0.009) and a lower mortality (7 vs 29.4%; p=0.001). There was no significant difference in blood loss or transfusion requirements between the two groups. The predicted EuroSCORE risks of the <12h group was 6.66% and the observed mortality was 7% (p=0.865). The observed mortality of 29.4% in the >or=12h group was significantly higher than the predicted EuroSCORE risks of 7.59% (p<0.001). CONCLUSIONS: Patients requiring re-exploration for bleeding are at higher risk of adverse outcomes and this risk is increased if time to re-exploration is prolonged for 12h or longer.

A surgeon's case volume of oesophagectomy for cancer strongly influences the operative mortality rate.

OBJECTIVE: To assess if individual case volume of oesophagectomy for cancer influences the risk of mortality and long-term survival. METHODS: Between January 1994 and December 2005, 195 resections for oesophageal cancer were performed by nine surgeons in a single institution. Operative mortality, defined as in hospital death, was compared between the high-volume and low-volume surgeons. Multivariate logistic regression was used to analyze the risk factors for death between the two groups, also in the presence of covariates. RESULTS: There were 140 males and 55 females with mean age of 63.4 (32-84). Two high-volume surgeons performed 61% (118) of the operations with a mean of 11 per year compared to 4 per year in the low-volume group. The patients in the two groups were matched for age (63 years vs 64; p=0.53), sex (67 vs 79% male; p=0.07). Ivor Lewis resections were performed more frequently by high-volume surgeons (95 vs 73%; p<0.001). The operative mortality rate was much lower when high case volume surgeons performed the procedure (4 vs 17%; p=0.001). The relative risk of death when low-volume surgeons performed the procedure was 4.59 (95% CI 1.57-13.46; p<0.001). In-hospital mortality was significantly associated with low-volume surgeon when controlling separately for age (OR 4.60; 95% CI 1.55, 13.60, p=0.006), tumor stage (OR 3.76; 95% CI 1.24, 11.45, p=0.02) and tumor type (OR 3.87; 95% CI 1.29, 11.60, p=0.016). Kaplan-Meier curves comparing the survival of high- and low-volume surgeons showed no statistical differences (Log rank p=0.48). CONCLUSIONS: Operative mortality rate for oesophagectomy for cancer is strongly influenced by case volume and was 4.6-fold higher when performed by surgeons with low case volume. Patients with oesophageal cancer in need of an oesophagectomy may benefit from referral to a high-volume thoracic surgeon.

Response to the editorial by Dr Geraghty.

This article is written in response to the linked editorial by Dr Geraghty about the adaptive Pacing, graded Activity and Cognitive behaviour therapy; a randomised Evaluation (PACE) trial, which we led, implemented and published. The PACE trial compared four treatments for people diagnosed with chronic fatigue syndrome. All participants in the trial received specialist medical care. The trial found that adding cognitive behaviour therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. In this article, we suggest that Dr Geraghty's views are based on misunderstandings and misrepresentations of the PACE trial; these are corrected.

Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial.

BACKGROUND: The PACE trial found that, when added to specialist medical care (SMC), cognitive behavioural therapy (CBT), or graded exercise therapy (GET) were superior to adaptive pacing therapy (APT) or SMC alone in improving fatigue and physical functioning in people with chronic fatigue syndrome 1 year after randomisation. In this pre-specified follow-up study, we aimed to assess additional treatments received after the trial and investigate long-term outcomes (at least 2 years after randomisation) within and between original treatment groups in those originally included in the PACE trial. METHODS: The PACE trial was a parallel-group randomised controlled trial of patients meeting Oxford criteria for chronic fatigue syndrome who were recruited from six secondary care clinics in the UK between March 18, 2005, and Nov 28, 2008. Participants were randomly allocated to receive SMC alone or plus APT, CBT, or GET. Primary outcomes (were fatigue measured with Chalder fatigue questionnaire score and physical functioning with short form-36 subscale score, assessed 1 year after randomisation. In this long-term follow-up, we sent postal questionnaires to assess treatment received after the trial and outcomes a minimum of 2 years after randomisation. We assessed long-term differences in outcomes within and between originally randomised groups. The PACE trial is registered at http://isrctn.org, number ISRCTN54285094. FINDINGS: Between May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires. Median time from randomisation to return of long-term follow-up assessment was 31 months (IQR 30-32; range 24-53). 210 (44%) participants received additional treatment (mostly CBT or GET) after the trial; with participants originally assigned to SMC alone (73 [63%] of 115) or APT (60 [50%] of 119) more likely to seek treatment than those originally assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0·0001). Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained (within-group comparison of fatigue and physical functioning, respectively, at long-term follow-up as compared with 1 year: CBT -2·2 [95% CI -3·7 to -0·6], 3·3 [0·02 to 6·7]; GET -1·3 [-2·7 to 0·1], 0·5 [-2·7 to 3·6]). Participants allocated to APT and to SMC alone in the trial improved over the follow-up period compared with 1 year (fatigue and physical functioning, respectively: APT -3·0 [-4·4 to -1·6], 8·5 [4·5 to 12·5]; SMC -3·9 [-5·3 to -2·6], 7·1 [4·0 to 10·3]). There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up. INTERPRETATION: The beneficial effects of CBT and GET seen at 1 year were maintained at long-term follow-up a median of 2·5 years after randomisation. Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment. Future research should identify predictors of response to CBT and GET and also develop better treatments for those who respond to neither. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, King's College London.

Rehabilitative therapies for chronic fatigue syndrome: a secondary mediation analysis of the PACE trial.

BACKGROUND: Cognitive behaviour therapy (CBT) added to specialist medical care (SMC), or graded exercise therapy (GET) added to SMC, are more effective in reducing fatigue and improving physical function than both adaptive pacing therapy (APT) plus SMC and SMC alone for chronic fatigue syndrome. We investigate putative treatment mechanisms. METHODS: We did a planned secondary mediation analysis of the PACE trial comparing SMC alone or SMC plus APT with SMC plus CBT and SMC plus GET for patients with chronic fatigue syndrome. 641 participants were recruited from six specialist chronic fatigue syndrome clinics in the UK National Health Service between March 18, 2005, and Nov 28, 2008. We assessed mediation using the product of coefficients method with the 12 week measure of the mediators and the 52 week measure of the outcomes. The primary outcomes were fatigue measured by the Chalder fatigue scale and physical function measured by the physical function subscale of the SF-36. We included confounder covariates and used treatment by mediator interaction terms to examine differences in mediator-outcome relations by treatment group. FINDINGS: The largest mediated effect for both CBT and GET and both primary outcomes was through fear avoidance beliefs with an effect of larger magnitude for GET (standardised effects ×10, CBT vs APT, fatigue -1.22, 95% CI -0.52 to -1.97, physical function 1.54, 0.86 to 2.31; GET vs APT, fatigue -1.86, -0.80 to -2.89, physical function 2.35, 1.35 to 3.39). Increase in exercise tolerance (6 min walk distance) was a potent mediator of the effect of GET (vs APT, fatigue -1.37, 95% CI -0.76 to -2.21, physical function 1.90, 1.10 to 2.91), but not CBT. INTERPRETATION: Our main finding was that fear avoidance beliefs were the strongest mediator for both CBT and GET. Changes in both beliefs and behaviour mediated the effects of both CBT and GET, but more so for GET. The results support a treatment model in which both beliefs and behaviour play a part in perpetuating fatigue and disability in chronic fatigue syndrome. FUNDING: UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, Department for Work and Pensions, National Institute for Health Research (NIHR), NIHR Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust, and Institute of Psychiatry, Psychology, and Neuroscience, King's College London.

Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: a cost-effectiveness analysis.

BACKGROUND: The PACE trial compared the effectiveness of adding adaptive pacing therapy (APT), cognitive behaviour therapy (CBT), or graded exercise therapy (GET), to specialist medical care (SMC) for patients with chronic fatigue syndrome. This paper reports the relative cost-effectiveness of these treatments in terms of quality adjusted life years (QALYs) and improvements in fatigue and physical function. METHODS: Resource use was measured and costs calculated. Healthcare and societal costs (healthcare plus lost production and unpaid informal care) were combined with QALYs gained, and changes in fatigue and disability; incremental cost-effectiveness ratios (ICERs) were computed. RESULTS: SMC patients had significantly lower healthcare costs than those receiving APT, CBT and GET. If society is willing to value a QALY at £30,000 there is a 62.7% likelihood that CBT is the most cost-effective therapy, a 26.8% likelihood that GET is most cost effective, 2.6% that APT is most cost-effective and 7.9% that SMC alone is most cost-effective. Compared to SMC alone, the incremental healthcare cost per QALY was £18,374 for CBT, £23,615 for GET and £55,235 for APT. From a societal perspective CBT has a 59.5% likelihood of being the most cost-effective, GET 34.8%, APT 0.2% and SMC alone 5.5%. CBT and GET dominated SMC, while APT had a cost per QALY of £127,047. ICERs using reductions in fatigue and disability as outcomes largely mirrored these findings. CONCLUSIONS: Comparing the four treatments using a health care perspective, CBT had the greatest probability of being the most cost-effective followed by GET. APT had a lower probability of being the most cost-effective option than SMC alone. The relative cost-effectiveness was even greater from a societal perspective as additional cost savings due to reduced need for informal care were likely.