The psychosocial impact of microtia and ear reconstruction: A national data-linkage study

IntroductionChildren with visible facial differences are believed to be at increased risk of negative psychosocial behaviours which may manifest as affective disorders. The aim of this study was to determine whether a diagnosis of microtia, and the associated surgical intervention, is associated with psychosocial implications including impaired educational attainment and a diagnosis of an affective disorder.MethodsA retrospective case-control study was conducted using data linkage to identify patients in Wales with a diagnosis of microtia. Matched controls were sought on the basis of age, gender and socioeconomic deprivation status to yield a total sample size of 709. incidence was calculated using annual and geographic birth rates. Surgical operation codes were used to classify patients into those that had no surgery, autologous reconstruction or prosthetic reconstruction. Educational attainment at 11 years of age, plus a diagnosis of depression or anxiety were used as markers of adverse psychosocial outcomes and the relative risk was attained using logistic regression analyses.ResultsThere were no significant associations between a diagnosis of microtia and an increased risk of adverse educational attainment or a risk of an affective disorder diagnosis. Male gender and higher deprivation scores were significantly associated with poorer educational attainment, irrespective of a diagnosis of microtia. Surgical intervention of any nature was also not associated with any increased risk of adverse educational or psychosocial outcomes in microtia patients.DiscussionMicrotia patients in Wales do not appear to be at greater risk of developing affective disorders or impaired academic performance as a result of their diagnosis or associated surgical intervention. Whilst reassuring, the need for appropriate support mechanisms to maintain positive psychosocial wellbeing and academic achievement in this patient cohort is reinforced

Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial

The trial recruits men with locally advanced or metastatic prostate cancer starting standard long-term hormone therapy. There are 5 research arms and 1 control arm. The trial has a pilot stage assessing safety and feasibility, 3 intermediate “activity” stages (I-III) where the outcome measure is failure-free survival (FFS) and one final “efficacy” stage (IV) with overall survival as primary outcome measure. At the end of each stage, each research arm is formally compared pairwise to the control arm. Accrual of further patients is discontinued early for any research arm either not showing sufficient evidence of activity or with adverse safety considerations; accrual continues to arms showing activity with acceptable safety. The stopping guideline compares the treatment effect against a pre-defined cut-off value using the hazard ratio when the hazards are proportional and restricted-mean survival time otherwise. This interim hurdle becomes increasingly stringent stage-by-stage. The addition of new research arm(s) can be actively considered when sufficiently interesting agents emerge. New research arms are compared only to contemporaneously-recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is independent of any of the original research arms stopping accrual early subject to adequate recruitment to support the overall trial aims

Estimating the global cost of vision impairment and its major causes: protocol for a systematic review

Introduction: Vision impairment (VI) places a burden on individuals, health systems and society in general. In order to support the case for investing in eye health services, an updated cost of illness study that measures the global impact of VI is necessary. To perform such a study, a systematic review of the literature is needed. Here we outline the protocol for a systematic review to describe and summarise the costs associated with VI and its major causes. Methods and analysis: We will systematically search in Medline (Ovid) and the Centre for Reviews and Dissemination database which includes the National Health Service Economics Evaluation Database. No language or geographical restriction will be applied. Additional literature will be identified by reviewing the references in the included studies and by contacting field experts. Grey literature will be considered. The review will include any study published from 1 January 2000 to November 2019 that provides information about costs of illness, burden of disease and/or loss of well-being in participants with VI due to an unspecified cause or due to one of the seven leading causes globally. Two reviewers will independently screen studies and extract relevant data from included studies. Methodological quality of economic studies will be assessed based on the British Medical Journal checklist for economic submissions adapted to costs of illness studies. This protocol has been prepared following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols and has been published prospectively in Open Science Framework. Ethics and dissemination Formal ethical approval is not required, as primary data will not be collected in this review. The findings of this study will be disseminated through peer-reviewed publications, stakeholder meetings and inclusion in the ongoing Lancet Global Health Commission on Global Eye Health. Registration details https://osf.io/9au3w (DOI 10.17605/OSF.IO/6F8VM)

The economics of vision impairment and its leading causes: A systematic review

Vision impairment (VI) can have wide ranging economic impact on individuals, households, and health systems. The aim of this systematic review was to describe and summarise the costs associated with VI and its major causes. We searched MEDLINE (16 November 2019), National Health Service Economic Evaluation Database, the Database of Abstracts of Reviews of Effects and the Health Technology Assessment database (12 December 2019) for partial or full economic evaluation studies, published between 1 January 2000 and the search dates, reporting cost data for participants with VI due to an unspecified cause or one of the seven leading causes globally: cataract, uncorrected refractive error, diabetic retinopathy, glaucoma, age-related macular degeneration, corneal opacity, trachoma. The search was repeated on 20 January 2022 to identify studies published since our initial search. Included studies were quality appraised using the British Medical Journal Checklist for economic submissions adapted for cost of illness studies. Results were synthesized in a structured narrative. Of the 138 included studies, 38 reported cost estimates for VI due to an unspecified cause and 100 reported costs for one of the leading causes. These 138 studies provided 155 regional cost estimates. Fourteen studies reported global data; 103/155 (66%) regional estimates were from high-income countries. Costs were most commonly reported using a societal (n = 48) or healthcare system perspective (n = 25). Most studies included only a limited number of cost components. Large variations in methodology and reporting across studies meant cost estimates varied considerably. The average quality assessment score was 78% (range 35–100%); the most common weaknesses were the lack of sensitivity analysis and insufficient disaggregation of costs. There was substantial variation across studies in average treatment costs per patient for most conditions, including refractive error correction (range $12–$201 ppp), cataract surgery (range $54–$3654 ppp), glaucoma (range $351–$1354 ppp) and AMD (range $2209–$7524 ppp). Future cost estimates of the economic burden of VI and its major causes will be improved by the development and adoption of a reference case for eye health. This could then be used in regular studies, particularly in countries with data gaps, including low- and middle-income countries in Asia, Eastern Europe, Oceania, Latin America and sub-Saharan Africa

Causal inference with randomised clinical trials of chemotherapy: The importance of well-documented treatment side-effects

Introduction Randomised Controlled Trials (RCTs) are universally considered as the most reliable way to demonstrate and assess causal relationships between treatments and outcome; science-based medicine is rooted in them. Spurious relationships between the outcome and a timefixed treatment-variable are eliminated by randomising patients over two or more arms of the trial. Hence, the randomisation procedure initiates the process by which treatment and outcomes of interest should be interpreted in a causal way. However, treatment is not always administered as intended, not least because of the occurrence of side effects and adverse events. In RCTs of chemotherapy, for example, the treatment administered may differ from the intended one because of the application of either cycle delays or dose reductions. Background Opposite to the∗intention-to-treat approach∗, a statistical analysis based on actual treatment data might be problematic due to the presence of the so-called∗treatment-adjustment bias∗. Exposure to chemotherapy agents may in fact be reduced and/or delayed as a consequence of previous-treatment side-effects. In particular, both reductions and delays contribute to lowering the value of the so-called Received Dose Intensity. Methods Inverse Probability-of-Treatment Weighting (IPTW) is a general methodology for removing treatment-adjustment bias. Working under the hypothesis of∗No Unmeasured Confounding∗, it creates a pseudopopulation by weighting each patient with the inverse probability of observing a certain treatment administration given the past treatment and toxicity history. However, a review of data collected from RCTs on osteosarcoma suggests that treatment side-effects may not be sufficiently well-documented. The pseudo-population created by IPTW has the following two properties: 1. Pseudo-patients' past toxicity-history no longer predicts exposure to chemotherapy in the next cycle; 2. The causal effect of treatment modifications on outcome is the same in both original and pseudopopulations. Results Using data from Medical Research Council trial BO06 (European Organisation for Research and Treatment of Cancer trial 80931) we will illustrate the use of IPTW and Marginal Structural Models (MSMs) for estimating the causal effect of dose reductions on Event-free Survival (EFS). The use of IPTW and MSMs allows to move beyond intention-to-treat and unbiasedly estimate the effect of treatment modifications on EFS. Conclusions We demonstrate that, even with complex and entangled data such as those collected in a RCT of chemotherapy, constructing and estimating a causal model is possible, provided that side-effects are well documented. When this is not the case, the removal of treatmentadjustment bias via IPTW might be problematic, if not prevented at all by the presence of unmeasured confounder. As such, good-quality toxicity data should be regarded as important enablers of causal modelling in RCTs of chemotherapy

Causal inference with randomised clinical trials of chemotherapy: The importance of well-documented treatment side-effects

Introduction Randomised Controlled Trials (RCTs) are universally considered as the most reliable way to demonstrate and assess causal relationships between treatments and outcome; science-based medicine is rooted in them. Spurious relationships between the outcome and a timefixed treatment-variable are eliminated by randomising patients over two or more arms of the trial. Hence, the randomisation procedure initiates the process by which treatment and outcomes of interest should be interpreted in a causal way. However, treatment is not always administered as intended, not least because of the occurrence of side effects and adverse events. In RCTs of chemotherapy, for example, the treatment administered may differ from the intended one because of the application of either cycle delays or dose reductions. Background Opposite to the∗intention-to-treat approach∗, a statistical analysis based on actual treatment data might be problematic due to the presence of the so-called∗treatment-adjustment bias∗. Exposure to chemotherapy agents may in fact be reduced and/or delayed as a consequence of previous-treatment side-effects. In particular, both reductions and delays contribute to lowering the value of the so-called Received Dose Intensity. Methods Inverse Probability-of-Treatment Weighting (IPTW) is a general methodology for removing treatment-adjustment bias. Working under the hypothesis of∗No Unmeasured Confounding∗, it creates a pseudopopulation by weighting each patient with the inverse probability of observing a certain treatment administration given the past treatment and toxicity history. However, a review of data collected from RCTs on osteosarcoma suggests that treatment side-effects may not be sufficiently well-documented. The pseudo-population created by IPTW has the following two properties: 1. Pseudo-patients' past toxicity-history no longer predicts exposure to chemotherapy in the next cycle; 2. The causal effect of treatment modifications on outcome is the same in both original and pseudopopulations. Results Using data from Medical Research Council trial BO06 (European Organisation for Research and Treatment of Cancer trial 80931) we will illustrate the use of IPTW and Marginal Structural Models (MSMs) for estimating the causal effect of dose reductions on Event-free Survival (EFS). The use of IPTW and MSMs allows to move beyond intention-to-treat and unbiasedly estimate the effect of treatment modifications on EFS. Conclusions We demonstrate that, even with complex and entangled data such as those collected in a RCT of chemotherapy, constructing and estimating a causal model is possible, provided that side-effects are well documented. When this is not the case, the removal of treatmentadjustment bias via IPTW might be problematic, if not prevented at all by the presence of unmeasured confounder. As such, good-quality toxicity data should be regarded as important enablers of causal modelling in RCTs of chemotherapy

Flexible trial design in practice - stopping arms for lack-of-benefit and adding research arms mid-trial in STAMPEDE: a multi-arm multi-stage randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial.</p> <p>Methods</p> <p>STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate ‘activity’ stages (focus: failure-free survival), and a final ‘efficacy’ stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims.</p> <p>Results</p> <p>(1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design.</p> <p>(2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies.</p> <p>Conclusions</p> <p>The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner.</p> <p>Trial registration</p> <p>ISRCTN78818544, NCT00268476</p> <p>First patient into trial: 17 October 2005</p> <p>First patient into abiraterone comparison: 15 November 2011</p

Quality of life of patients with osteosarcoma in the european american osteosarcoma study-1 (EURAMOS-1) : Development and implementation of a questionnaire substudy

Background: The quality of life (QoL) of patients with osteosarcoma (OS) may be adversely affected by the disease or its treatment. Therefore, it is important to understand the QoL of patients undergoing treatment for OS to improve the QoL. We report on the first prospective international QoL study that was embedded within a large randomized clinical trial from 4 national study groups. Objective: This paper aimed to describe the QoL study development, methodology, accrual details, and characteristics of the QoL cohort. Methods: A total of 2260 patients registered in the EURopean AMerican Osteosarcoma Study-1 (EURAMOS-1), of whom 97.92% (2213/2260) were eligible for the optional QoL assessment and could participate in terms of questionnaire availability. Overall, 61.86% (1369/2213) of patients and/or proxies completed the QoL evaluation at the first assessment time point (E1) after the start of preoperative treatment. The QoL measures used (self- and/or proxy reports) depending on the patient’s age and national study group. Participants and nonparticipants in the ancillary QoL study were compared regarding relevant demographic and disease-related characteristics at registration in the trial. Results: The participation rate at time point E1 did not differ with regard to age, gender, the occurrence of pathological fracture, or the presence of any metastases at diagnosis. No differences were found regarding the primary tumor site. Only the national study group affiliation had an influence on participation. Participation decreased linearly with trial progress up to 20% at the final time point of QoL assessment. Conclusions: This study demonstrates the feasibility of international cooperation for the purpose of assessing and understanding the QoL of pediatric and adolescent/young adult patients with cancer. Future outcomes of this QoL substudy will help to adapt interventions to improve QoL

Quality of Life of Patients With Osteosarcoma in the European American Osteosarcoma Study-1 (EURAMOS-1): Development and Implementation of a Questionnaire Substudy

The quality of life (QoL) of patients with osteosarcoma (OS) may be adversely affected by the disease or its treatment. Therefore, it is important to understand the QoL of patients undergoing treatment for OS to improve the QoL. We report on the first prospective international QoL study that was embedded within a large randomized clinical trial from 4 national study groups. This paper aimed to describe the QoL study development, methodology, accrual details, and characteristics of the QoL cohort. A total of 2260 patients registered in the EURopean AMerican Osteosarcoma Study-1 (EURAMOS-1), of whom 97.92% (2213/2260) were eligible for the optional QoL assessment and could participate in terms of questionnaire availability. Overall, 61.86% (1369/2213) of patients and/or proxies completed the QoL evaluation at the first assessment time point (E1) after the start of preoperative treatment. The QoL measures used (self- and/or proxy reports) depending on the patient’s age and national study group. Participants and nonparticipants in the ancillary QoL study were compared regarding relevant demographic and disease-related characteristics at registration in the trial. The participation rate at time point E1 did not differ with regard to age, gender, the occurrence of pathological fracture, or the presence of any metastases at diagnosis. No differences were found regarding the primary tumor site. Only the national study group affiliation had an influence on participation. Participation decreased linearly with trial progress up to 20% at the final time point of QoL assessment. This study demonstrates the feasibility of international cooperation for the purpose of assessing and understanding the QoL of pediatric and adolescent/young adult patients with cancer. Future outcomes of this QoL substudy will help to adapt interventions to improve QoL