Power and sample-size calculations for trials that compare slopes over time: Introducing the slopepower command.

Trials of interventions that aim to slow disease progression may analyze a continuous outcome by comparing its change over time—its slope—between the treated and the untreated group using a linear mixed model. To perform a sample-size calculation for such a trial, one must have estimates of the parameters that govern the between- and within-subject variability in the outcome, which are often unknown. The algebra needed for the sample-size calculation can also be complex for such trial designs. We have written a new user-friendly command, slopepower, that performs sample-size or power calculations for trials that compare slope outcomes. The package is based on linear mixed-model methodology, described for this setting by Frost, Kenward, and Fox (2008, Statistics in Medicine 27: 3717–3731). In the first stage of this approach, slopepower obtains estimates of mean slopes together with variances and covariances from a linear mixed model fit to previously collected user-supplied data. In the second stage, these estimates are combined with user input about the target effectiveness of the treatment and design of the future trial to give an estimate of either a sample size or a statistical power. In this article, we present the slopepower command, briefly explain the methodology behind it, and demonstrate how it can be used to help plan a trial and compare the sample sizes needed for different trial designs

Linked symptom monitoring and depression treatment programmes for specialist cancer services: protocol for a mixed-methods implementation study.

INTRODUCTION: There is growing awareness that cancer services need to address patients' well-being as well as treating their cancer. We developed systematic approaches to (1) monitoring patients' symptoms including depression using a 'Symptom Monitoring Service' and (2) providing treatment for those with major depression using a programme called 'Depression Care for People with Cancer'. Used together, these two programmes were found to be highly effective and cost-effective in clinical trials. The overall aims of this project are to: (1) study the process of introducing these programmes into routine clinical care in a large cancer service, (2) identify the challenges associated with implementation and how these are overcome, (3) determine their effectiveness in a routine non-research setting and (4) describe patients' and clinicians' experience of the programmes. METHODS AND ANALYSIS: This is a mixed-methods longitudinal implementation study. We will study the process of implementation in three phases (April 2016-December 2018): 'Pre-implementation' (setting up of the new programmes), 'Early Implementation' (implementation of the programmes in a small number of clinics) and 'Implementation and Maintenance' (implementation in the majority of clinics). We will use the following methods of data collection: (1) contemporaneous logs of the implementation process, (2) interviews with healthcare professionals and managers, (3) interviews with patients and (4) routinely collected clinical data. ETHICS AND DISSEMINATION: The study has been reviewed by a joint committee of Oxford University Hospitals National Health Service Foundation Trust Research and Development Department and the University of Oxford's Clinical Trials and Research Governance Department and judged to be service evaluation, not requiring ethics committee approval. The findings of this study will guide the scaling up implementation of the programmes across the UK and will enable us to construct an implementation toolkit. We will disseminate our findings in publications and at relevant national and international conferences

How the EMERGE guideline on medication adherence can improve the quality of clinical trials.

Medication adherence in drug trials is suboptimal, affecting the quality of these studies and adding significant costs. Nonadherence in this setting can lead to null findings, unduly large sample sizes and the need for dose modification after a drug has been approved. Despite these drawbacks, adherence behaviours are not consistently measured, analysed or reported appropriately in trial settings. The ESPACOMP Medication Adherence Reporting Guideline (EMERGE) offers a solution by facilitating a sound protocol design that takes this crucial factor into account. This article summarises key evidence on traditional and newer measurements of adherence, discusses implementation in clinical trial settings and makes recommendations about the analysis and interpretation of adherence data. Given the potential benefits of this approach, the authors call on regulators and the pharmaceutical industry to endorse the EMERGE guideline

Classifying atopic dermatitis: protocol for a systematic review of subtypes (phenotypes) and associated characteristics.

INTRODUCTION: Atopic dermatitis is a complex disease with differing clinical presentations. Many attempts have been made to identify uniform subtypes, or phenotypes, of atopic dermatitis in order to identify different aetiologies, improve diagnosis, estimate more accurate clinical prognoses, inform treatment andmanagement or predict treatment efficacy andeffectiveness. However, no consensus yet exists on exactly what defines these phenotypes or how many there are and whether they are genuine or statistical artefacts. This review aims to identify previously reported phenotypes of atopic dermatitis, the features used to define them and any characteristics or clinical outcomes significantly associated with them. METHODS AND ANALYSIS: We will search Ovid Embase, Ovid MEDLINE and Web of Science from inception to the latest available date at the time of the search for studies attempting to classify atopic dermatitis in humans using any cross-sectional or longitudinal epidemiological or interventional design. Primary outcomes are atopic dermatitis phenotypes, features used to define them and characteristics associated with them in subsequent analyses. A secondary outcome is the methodological approach used to derive them. Two reviewers will independently screen titles and abstracts for inclusion, extract data and assess study quality. We will present the results of this review descriptively and with frequencies where possible. ETHICS AND DISSEMINATION: Ethical approval is not required for this study as it is a systematic review. We will report results from this systematic review in a peer-reviewed journal. The main value of this study will be to inform further research. PROSPERO REGISTRATION NUMBER: CRD42018087500

Unbiased and automated identification of a circulating tumour cell definition that associates with overall survival

Circulating tumour cells (CTC) in patients with metastatic carcinomas are associated with poor survival and can be used to guide therapy. Classification of CTC however remains subjective, as they are morphologically heterogeneous. We acquired digital images, using the CellSearch™ system, from blood of 185 castration resistant prostate cancer (CRPC) patients and 68 healthy subjects to define CTC by computer algorithms. Patient survival data was used as the training parameter for the computer to define CTC. The computer-generated CTC definition was validated on a separate CRPC dataset comprising 100 patients. The optimal definition of the computer defined CTC (aCTC) was stricter as compared to the manual CellSearch CTC (mCTC) definition and as a consequence aCTC were less frequent. The computer-generated CTC definition resulted in hazard ratios (HRs) of 2.8 for baseline and 3.9 for follow-up samples, which is comparable to the mCTC definition (baseline HR 2.9, follow-up HR 4.5). Validation resulted in HRs at baseline/follow-up of 3.9/5.4 for computer and 4.8/5.8 for manual definitions. In conclusion, we have defined and validated CTC by clinical outcome using a perfectly reproducing automated algorithm

Atopic eczema and cancer: parallel cohort studies in England and Denmark

IMPORTANCE: Associations between atopic eczema and cancer are unclear, with competing theories: that increased immune surveillance reduces cancer risk; and that immune stimulation increases risk. Establishing baseline cancer risk in people with atopic eczema is important prior to exploring the impact of new biologic drugs (for eczema) on cancer risk. OBJECTIVE: To investigate whether atopic eczema is associated with cancer. DESIGN: Matched cohort studies (England: 1998-2016; Denmark: 1982-2016). SETTING: English primary care, and nationwide Danish data. PARTICIPANTS: Individuals with atopic eczema (England: adults only; Denmark: any age) matched on age, sex, calendar period, and (in England only) primary care practice, to people without eczema. EXPOSURE: Atopic eczema MAIN OUTCOMES: We compared overall risk of cancer, and of 11 specific cancers, in people with and without eczema. RESULTS: We included 471,970 and 2,239,775 individuals with and without atopic eczema respectively in England; and 44,945 and 445,673 respectively in Denmark. We found little evidence of associations between atopic eczema and cancer overall (adjusted hazard ratios [HRs] [99%CI]: England 1.04 [1.02-1.06]; Denmark 1.05 [0.95-1.16]), or for most specific cancers. However, non-cutaneous lymphoma risk was raised in people with atopic eczema in England (adjusted HR [99%CI] 1.20 [1.07-1.34] for non-Hodgkin’s [NHL] and 1.48 [1.07-2.04] for Hodgkin’s). Lymphoma risk increased with greater eczema severity (NHL adjusted HR [99%CI] compared to without eczema: mild 1.06 [0.90-1.25], moderate 1.24 [1.04-1.48], severe 2.08 [1.42-3.04]). Danish point estimates also showed increased lymphoma in moderate-to-severe eczema compared to without (adjusted HR [99%CI]: NHL 1.31 [0.76-2.26]; Hodgkin’s 1.35 [0.65-2.28]), but confidence intervals were wide. CONCLUSIONS AND RELEVANCE: Our findings, from two large population-based studies in different settings, are largely reassuring as they do not support associations between eczema and most cancers. However, we observed an association between eczema and lymphoma that increased with eczema severity, which warrants further study with the introduction of new therapeutics that may impact cancer risk

Changes in Mental Health Needs during COVID-19 in the Republic of Georgia: A Longitudinal Follow-up Study

BACKGROUND: To examine changes in COVID-19 stressors and symptoms of mental disorders in the Republic of Georgia. METHODS: A longitudinal design was used. Following on from our study of May-June 2020, this follow-up study in January-March 2021 was conducted at: (i)an individual level with the same respondents involved in the May-June 2020 study (repeat responders/cohort); and (ii) at a population-wide level, using non-probabilistic sampling. Questionnaire sections covered: (i)demographic, socio-economic characteristics; (ii)level of burden caused by COVID-19-related stressors/concern; and (iii)symptoms of anxiety(GAD-7), depression(PHQ-9), PTSD(ITQ), adjustment disorder(ADNM8). Descriptive and multivariable regression analyses were conducted. RESULTS: Among population-level survey respondents(N=1195), the probability of reporting mental ill health symptoms increased in 2021 compared to 2020 for PTSD(OR1.82), depression(OR1.40), adjustment disorder(OR 1.80), and marginally for anxiety(OR1.17). For the individual repeat respondents(N=455), the probability increased for depression(OR1.88) and adjustment disorder(OR2.56). The perceived burden of pandemic concern worsened in 2021 compared to 2020 for almost all stressors, particularly around access to health care, infecting others, and conflict in the home. PTSD was associated with an increased concern score from 2020 to 2021. CONCLUSION: Our study highlights the need to strengthen response strategies to address the elevated mental health needs related to COVID-19 in Georgia. It recommends increasing accessibility of early interventions and the need to modernise mental health services to strengthen access to care. It also calls for monitoring patterns of mental health disorders for better understanding and responses to mental health needs in Georgia

MAJOR DEPRESSION AND SURVIVAL IN PEOPLE WITH CANCER

OBJECTIVE: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. METHODS: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. RESULTS: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15-1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11-1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08-1.71), lung cancer (HR = 1.39, 95% CI = 1.24-1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08-2.85). The pooled HR was 1.41 (95% CI = 1.29-1.54, p < .001, I2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer. CONCLUSIONS: Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study

Factors associated with depression, anxiety, and severe mental illness among adults with atopic eczema or psoriasis: a systematic review and meta-analysis

Background: Evidence suggests an association between atopic eczema (AE) or psoriasis and mental illness. However, factors associated with mental illness are unclear. / Objectives: To synthesise and evaluate all available evidence on factors associated with depression, anxiety, and severe mental illness (SMI) among adults with AE or psoriasis. / Methods: We searched electronic databases, grey literature databases, and clinical trial registries from inception to February 2022 for studies in adults with AE or psoriasis. Eligible studies were randomised controlled trials (RCTs), cohort, cross-sectional or case-control studies where effect estimates of factors associated with depression, anxiety, or SMI were reported. We did not apply language or geographical restrictions. We assessed risk of bias using the Quality in Prognosis Studies tool. We synthesised results narratively, and if at least two studies were sufficiently homogenous, we pooled effect estimates in a random-effects meta-analysis. / Results: We included 21 studies (11 observational, 10 RCT). No observational studies in AE fulfilled our eligibility criteria. Observational studies in people with psoriasis mostly investigated factors associated with depression or anxiety – one cross-sectional study investigated factors associated with schizophrenia. Pooled effect estimates suggest being female, and psoriatic arthritis, were associated with depression (female sex:OR = 1.62,95%CI = 1.09-2.40,95%PI = 0.62-4.23, I2 = 24.90%, Tau2 = 0.05; psoriatic arthritis:OR = 2.26,95%CI = 1.56-3.25,95%PI = 0.21-24.23, I2 = 0.00%, Tau2 = 0.00) and anxiety (female sex:OR = 2.59,95%CI = 1.32-5.07,95%PI = 0.00-3956.27, I2 = 61.90%, Tau2 = 0.22; psoriatic arthritis:OR = 1.98,95%CI = 1.33-2.94, I2 = 0.00%, Tau2 = 0.00). Moderate/severe psoriasis was associated with anxiety (OR = 1.14,95%CI = 1.05-1.25, I2 = 0.00%, Tau2 = 0.00), but not depression. Evidence from RCTs suggested adults with AE or psoriasis given placebo had higher depression and anxiety scores compared to comparators given targeted treatment (e.g., biologic agents). / Conclusions: Our review highlights limited existing research on factors associated with depression, anxiety, and SMI in adults with AE or psoriasis. Observational evidence on factors associated with depression or anxiety in people with psoriasis was conflicting or from single studies, but some identified factors were consistent with those in the general population. Evidence on factors associated with SMIs in people with AE or psoriasis was particularly limited. Evidence from RCTs suggested AE and psoriasis treated with placebo was associated with higher depression and anxiety scores compared to skin disease treated with targeted therapy, however, follow-up was limited, therefore long-term effects on mental health are unclear

Atopic eczema and obesity: a population-based study

Background Atopic eczema is a common chronic inflammatory skin disease. Research suggests an association between atopic eczema and obesity, with inconsistent evidence from European populations. Objectives To explore the association between diagnosed atopic eczema and being overweight or obese, and whether increased atopic eczema severity was associated with higher body mass index. Methods We undertook a cross-sectional analysis within a matched (age, sex, GP practice) cohort of adults with and without a diagnosis of atopic eczema. We used primary care (Clinical Practice Research Datalink Gold) and linked hospital admissions data (1998-2016). We used conditional logistic regression to compare the odds of being overweight or obese (adjusting for confounders and potential mediators) in those with atopic eczema (mild, moderate and severe, and all eczema) to those without. Results We identified 441,746 people with atopic eczema, matched to 1,849,722 without. People with atopic eczema had slightly higher odds of being overweight or obese compared to those without (OR 1.08, 95% CI 1.07, 1.09) after adjusting for age, asthma and socio-economic deprivation. Adjusting for potential mediators (high-dose glucocorticoids, harmful alcohol use, anxiety, depression, smoking) had minimal effect on effect estimates (OR 1.07, 95% CI 1.06, 1.08). We saw no evidence that odds of being overweight or obese increased with increasing atopic eczema severity, and there was no association in people with severe eczema. Conclusion We found evidence of a small overall association between atopic eczema and being overweight or obese. However, there was no association with obesity among those with the most severe eczema. Our findings are largely reassuring for this prevalent patient group that may already have an increased risk of cardiovascular disease