Statistical Analysis Plan Research Articles

Emotion dysregulation in youths with obsessive-compulsive disorder and its implication for treatment - an exploratory study from the TECTO trial: A protocol and statistical analysis plan

BackgroundResearch on improving psychotherapy for youths with obsessive-compulsive disorder (OCD), including cognitive behavioral therapy (CBT), should explore what works for whom and how by examining baseline moderators and potential mechanisms of change. Emotion dysregulation is proposed as an intermediate therapy factor in a transdiagnostic framework. This study investigates emotion dysregulation as an outcome, mechanism, and moderator of psychotherapy in youths aged 8-17 years with OCD. MethodsData are from a randomized clinical trial and a parallel prospective study of healthy controls. Participants with OCD (n=130; 121 in this study) were randomized to 14 sessions of either family-based CBT with exposure and response prevention versus family-based psychoeducation and relaxation training. We will; 1) assess if emotion dysregulation, measured by the Difficulties in Emotion Regulation Scale (DERS), decreases from baseline to end-of-treatment; 2) compare the proportion of participants with normative emotion regulation to a 90% reference interval from healthy controls (n=90); 3) use linear regression to examine if baseline emotion dysregulation moderates treatment effects measured by the Children’s Yale-Brown Obsessive-Compulsive Scale; 4) investigate if changes in emotion dysregulation mediate treatment effects; and 5) investigate the stability of emotion regulation over time in the healthy controls. Analyses 1-4 will be conducted for all OCD participants and separately for the two treatment groups. Two independent investigators will perform the analyses. ConclusionThis protocol and statistical analysis plan are presented to enhance analytical transparency and limit bias.

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study

Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n=16, nusinersen: n=154, both: n=2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).

Real-World Evidence BRIDGE: A Tool to Connect Protocol With Code Programming.

To enhance documentation on programming decisions in Real World Evidence (RWE) studies. We analyzed several statistical analysis plans (SAP) within the Vaccine Monitoring Collaboration for Europe (VAC4EU) to identify study design sections and specifications for programming RWE studies. We designed a machine-readable metadata schema containing study sections, codelists, and time anchoring definitions specified in the SAPs with adaptability and user-friendliness. We developed the RWE-BRIDGE, a metadata schema in form of relational database divided into four study design sections with 12 tables: Study Variable Definition (two tables), Cohort Definition (two tables), Post-Exposure Outcome Analysis (one table), and Data Retrieval (seven tables). We provide a guide to populate this metadata schema and a Shiny app that checks the tables. RWE-BRIDGE is available on GitHub (github.com/UMC-Utrecht-RWE/RWE-BRIDGE). The RWE-BRIDGE has been designed to support the translation of study design sections from statistical analysis plans into analytical pipelines and to adhere to the FAIR principles, facilitating collaboration and transparency between researcher and programmers. This metadata schema strategy is flexible as it can support different common data models and programming languages, and it is adaptable to the specific needs of each SAP by adding further tables or fields, if necessary. Modified versions of the RWE-BRIGE have been applied in several RWE studies within VAC4EU. RWE-BRIDGE offers a systematic approach to detailing variables, time anchoring, and algorithms for RWE studies. This metadata schema facilitates communication between researcher and programmers.

Maribavir for refractory cytomegalovirus infection (with or without resistance) in solid organ transplant recipients: subgroup analysis of the phase 3 randomized SOLSTICE study

In the phase 3 SOLSTICE study (NCT02931539), maribavir was superior to investigator-assigned therapy (IAT) for confirmed cytomegalovirus viremia clearance at study week 8 in hematopoietic cell/solid organ transplant (HCT/SOT) recipients. We report additional efficacy and safety analyses from the SOT subgroup. Eligible solid organ transplant recipients (n=211) received maribavir 400 mg twice daily (n=142) or IAT (n=69) for 8 weeks (12 weeks' follow-up). Cytomegalovirus viremia clearance at week 8 (primary endpoint) and cytomegalovirus viremia clearance plus symptom control at the end of week 8 maintained through week 16 (key secondary endpoint) were assessed. Graft outcomes and treatment-emergent adverse events were analyzed. A higher proportion maribavir-treated patients achieved the primary endpoint than with IAT across transplant organ types, including kidney (maribavir: 59.5%, IAT: 34.4%), lung (47.5%, 13.6%), and heart (42.9%, 11.1%). Similar proportions of patients achieved the key secondary endpoint in both arms (13.4% versus 11.6%; adjusted difference: 2.4%; 95% CI: -7.05, 11.83%; p=0.620). Rates of treatment-emergent adverse events were: maribavir (96.5%), IAT (88.4%). Maribavir (3.5%) had fewer treatment discontinuations due to treatment-emergent adverse events than IAT (23.2%). There were no graft losses; patients in both arms experienced acute rejection (maribavir: 9 [6.3%]; IAT: 4 [5.8%]). Treatment-emergent maribavir mutations occurred in 28.2% of patients; 19/33 patients achieved viremia clearance with subsequent alternative treatment. Consistent with findings in the overall SOLSTICE population, this subgroup analysis of SOT recipients demonstrated greater effectiveness of maribavir for cytomegalovirus viremia clearance and fewer discontinuations due to treatment-emergent adverse events than IAT. ClinicalTrials.gov; NCT02931539 DATA AVAILABILITY STATEMENT: The datasets, including the redacted study protocol, redacted statistical analysis plan, and individual participants data supporting the results reported in this article, will be made available within three months from initial request, to researchers who provide a methodologically sound proposal. The data will be provided after its deidentification, in compliance with applicable privacy laws, data protection and requirements for consent and anonymization.

Do randomised clinical trials on dental caries adopt Open Science practices?

BackgroundOpen Science Practices (OSPs) are essential when assessing research integrity and quality of Randomised Clinical Trials (RCTs). As dental caries represents a significant oral health burden, our objective was to identify and analyse the adoption of OSPs within RCTs focused on addressing this disease.MethodsWe searched PubMed to retrieve RCTs related to dental caries published from January 2000 to March 2022. Two independent researchers assessed a random sample of these articles to evaluate their eligibility until reaching the minimum sample size. Then, the same examiners reviewed the included texts regarding the OSPs adopted in the articles. The collected variables related to OSPs were reporting guidelines, protocol registration, detailed methodology available, open-source software, statistical analysis code sharing, statistical analysis plan, data sharing, open peer review, and open access. Association analyses using logistic regression were conducted considering the publication year, the continent of the first author, impact factor and open-access policy of the journals (explanatory variables), and adoption of at least one OSP or one OSP other than open access (outcomes). The recommendations for adopting OSPs were assessed by reviewing the “Instructions for Authors” section of the most frequently used journals where the included papers were published.Results64.8% of the articles (95% Confidence Interval = 59.3–70.1%) adopted at least one OSP. However, no individual OSP was adopted by more than 50% of the articles. The most adopted practices were protocol registration (37.1%), the use of reporting guidelines (33.1%) and publishing open access (37.3%). These are also the OSPs most often recommended by journals in the Instructions for Authors. A few articles adopted other practices. Older articles presented a lower frequency of adopting these practices, and articles published in higher impact factor journals were positively associated with both outcomes.ConclusionThe RCTs published on dental caries demonstrate a low frequency of adoption of most OSPs. However, a trend toward increased adoption of these practices has been notable in recent years.

Protocol and Statistical Analysis Plan for a Comparative Interrupted Time Series Evaluation of the Impact of Deemed Consent for Organ Donation Legislative Reform in Nova Scotia, Canada.

The Canadian province of Nova Scotia recently became the first North American jurisdiction to implement deemed consent for deceased organ donation as part of a comprehensive legislative reform of their donation and transplantation system. This study will examine the performance metrics and effectiveness of this policy in comparison with other Canadian provinces via a natural experiment evaluation. We will use a cross-sectional controlled interrupted time series quasi-experimental design. Our primary outcome will be consent for deceased donation as confirmed at the time of eligibility (prior registered intent to donate will be noted but not be considered positive unless affirmed at the time of eligibility). Secondary outcomes will include identification and referral of patients who are potential donors, rates of family override of previously registered intent to donate, and donation and transplantation rates per million population. Data will be collected from potential donor audits in Nova Scotia and 3 control provinces (provinces in Canada without deemed consent policies). Study outcomes will be compared in Nova Scotia relative to control provinces in the 3 y before and 3 y after the implementation of legislative reform. These provinces were selected as having systems resembling those of Nova Scotia but without deemed consent.Using controlled interrupted time series methodology compared with other Canadian provinces with otherwise similar systems, we aim to isolate the impact of the deemed consent aspect of legislative reform in Nova Scotia using a robust natural experiment evaluation design as much as possible. Careful selection of outcome measures will allow donation and transplantation stakeholders to properly evaluate if similar reforms should be considered in their jurisdictions.

BN SO24 - Predicting incidental gallbladder cancer: A protocol for identifying predictive factors of incidentally detected gallbladder cancer and prospective validation of a scoring system to allow selective histological analysis of the gallbladder

Abstract Background Incidental Gallbladder Cancer (iGBC) is a rare complication of cholecystectomy, with a UK incidence of 0.14-0.3%. Despite its rarity, most gallbladder specimens are analysed histologically. Some comparable countries undertake Selective Histological Analysis (SHA), selecting high-risk specimens for histology based on clinical judgement or postoperative inspection. However, evidence suggests a third of diagnoses can be missed with these approaches. Swedish and Dutch diagnostic scores incorporate few risk factors and are not generalisable to the UK. We present a protocol for a UK study aiming to develop a detailed diagnostic score for iGBC to reliably stratify patients by their risk of iGBC. Method This UK multicentre, cross-sectional, trainee-led study includes adult patients undergoing cholecystectomy for benign indications. It incorporates a feasibility study and an adaptive design, and has been submitted for ethical review. A parallel qualitative study will explore attitudes towards the risk of iGBC and the acceptability of SHA among patients and healthcare professionals. The feasibility phase will include 500 patients over six months, collecting data on patient risk factors for iGBC, preoperative investigations, operative findings, and histology results. Exclusion criteria include cholecystectomy as a secondary procedure, polyps over 5mm, and conditions known to increase the risk of biliary tract cancers. Results Following the feasibility phase, the recruitment rate and data completeness will be evaluated. Outcomes will be assessed against anticipated values, and collaborators will be surveyed to identify challenges with data collection. Necessary adjustments to the electronic case record form or overall protocol will be made, and the recruitment target will be recalculated based on an updated sample size calculation. When the study meets specified progression criteria, additional sites will be recruited, and data collection will continue to meet the required sample size. A detailed statistical analysis plan will be provided at a later date. Conclusion This protocol describes a UK diagnostic modelling study aimed at developing a risk-stratification score for iGBC in patients undergoing routine cholecystectomy, identifying high-risk patients and facilitating SHA.

Statistical analysis plan for the FiO2-C trial: effects of closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) on outcomes of extremely preterm infants—a randomized-controlled parallel group multicentre trial for safety and efficacy

BackgroundExtremely low gestational age neonates (ELGANs, i.e. those born before 28 weeks postmenstrual age (PMA)) often require supplemental oxygen and frequently experience intermittent hypo- and hyperoxemic episodes. Exposure to episodes with inadequate oxygen concentrations has been shown to be associated with an increased risk of retinopathy of prematurity (ROP), bronchopulmonary dysplasia (BPD), necrotizing enterocolitis (NEC), neurodevelopmental impairment (NDI) and death. Closed-loop automatic control of the inspiratory fraction of oxygen (FiO2-C) reduces number and duration of hypo- and hyperoxemic episodes in ELGANs. Its impacts on clinically important short- and long-term outcomes such as ROP, BPD, NEC, NDI and mortality have not yet been studied.MethodsAn outcome-assessor-blinded, multicentre, randomized-controlled, parallel-group trial for superiority was designed to study the effects of FiO2-C (provided by standard infant ventilators) in addition to routine manual control (RMC) during respiratory support, compared to RMC only, on short- and long-term clinical outcomes in ELGANs. Two co-primary composite outcomes were defined: (i) death, severe ROP, BPD or NEC, assessed at 36 weeks PMA or, in case of ROP, until complete vascularization of the retina; (ii) death or NDI (defined as language/cognitive delay, motor impairment, severe visual impairment or hearing impairment), assessed at 2 years corrected age.ResultsPrimary outcomes will be compared between the two intervention groups using a Cochran-Mantel-Haenszel test. The factors considered for randomization (centre, sex and gestational age at birth (< 26 weeks and ≥ 26 weeks)) will be used to define strata. Results will be presented as adjusted odds ratios with two-sided 95% and 97.5% confidence intervals and two-sided p values.ConclusionsThe statistical analyses for the FiO2-C trial were defined in the study protocol and specified in detail in this statistical analysis plan published prior to any statistical analysis. This is in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines.Trial registrationClinicalTrials.gov NCT03168516. Registered on May 30, 2017.

Detailed statistical analysis plan for a guided self-determination intervention versus an attention control for outpatients with type 2 diabetes in the randomised OVERCOME trial

BackgroundAutonomy-supporting interventions may be a prerequisite to achieve better long-term management of type 2 diabetes. Evidence suggests that the guided self-determination (GSD) method might improve haemoglobin A1c and diabetes distress in people with type 1 diabetes. The evidence of an effect of a GSD intervention compared with an attention control group in adults with type 2 diabetes is unknown.Methods/designThe trial is designed as a pragmatic, investigator-initiated, dual-centre, randomised, parallel-group, assessor-blinded, superiority clinical trial of persons with type 2 diabetes. A nurse will administer GSD intervention versus an attention control. The primary outcome is diabetes distress, and secondary outcomes are quality of life, depressive symptoms, and non-serious adverse events. Exploratory outcomes are haemoglobin A1c, motivation, and serious adverse events. Participants are assessed at baseline, 5-, and 12-month follow-up. Here, we present a detailed, comprehensive plan of all statistical analyses, including methods to handle missing data, and assessments of the underlying statistical assumptions. The statistical analyses will be conducted independently by two statisticians following the present plan.DiscussionTo mitigate the risk of analysis bias and increase the validity of the OVEROME trial, this statistical analysis plan was developed prior to unblinding of the trial results in concordance with the Declaration of Helsinki and the Conference on Harmonization of Good Clinical Practice Guidelines.Trial registrationClinicalTrials.gov NCT 04601311. Registered on October 2020.

Effect of high-flow nasal therapy on patient-centred outcomes in patients at high risk of postoperative pulmonary complications after cardiac surgery: update to the statistical analysis plan for NOTACS, a multicentre adaptive randomised controlled trial

BackgroundThe NOTACS trial will assess the efficacy, safety and cost-effectiveness of high-flow nasal therapy (HFNT) compared to standard oxygen therapy (SOT) on the outcomes of patients after cardiac surgery.Methods/designNOTACS is an adaptive, international, multicentre, parallel group, randomised controlled trial, with a pre-planned interim sample size re-estimation (SSR). A minimum of 850 patients will be randomised 1:1 to receive either HFNT or SOT. The primary outcome is days alive and at home in the first 90 days after the planned surgery (DAH90), with a number of secondary analyses and cost-effectiveness analyses also planned. The interim SSR will take place after a minimum of 300 patients have been followed up for 90 days and will allow for the sample size to increase up to a maximum of 1280 patients.ResultsThis manuscript provides detailed descriptions of the design of the NOTACS trial and the analyses to be undertaken at the interim and final analyses. The main purpose of the interim analysis is to assess safety and to perform a sample size re-estimation. The main purpose of the final analysis is to examine the safety, efficacy and cost-effectiveness of HFNT compared to SOT on the outcomes of patients after cardiac surgery.DiscussionThis manuscript outlines the key features of the NOTACS statistical analysis plan and was submitted to the journal before the final analysis in order to preserve scientific integrity under an adaptive design framework. A previous version of this SAP was published prior to the interim analysis (Dawson, 2022). The NOTACS SAP closely follows published guidelines for the content of SAPs in clinical trials (Gamble, 2017).Trial registrationISRCTN14092678. (13 May 2020).

Adapting to change: experiences and recommendations from the Pain Management Collaboratory on modifying statistical analysis plans.

Best practices for clinical trials stipulate that statistical analysis plans (SAPs) need to be finalized before initiation of any analysis. However, there is limited guidance about when changes to SAPs are acceptable and how these changes should be incorporated into the research plan with appropriate documentation. We conducted a survey of 12 pragmatic clinical trials (PCTs) in the Pain Management Collaboratory that evaluated nonpharmacological interventions for pain to assess the following SAP information: (1) location of statistical analysis details, (2) types of statistical analyses planned, (3) sponsor requirements, (4) templates used for development, (5) publication plan, (6) changes since trial launch, (7) process of documenting changes, and (8) process of updating the trial registry. All 12 PCTs provided details of their SAPs for the primary outcomes in the institutional review board-approved trial protocol; 8 included plans for secondary outcomes, and 6 included plans for tertiary/exploratory outcomes. Most PCTs made SAP changes after trial initiation, many as a result of COVID-19-related issues. Eleven of the PCTs were actively recruiting participants. Changes were made to sample size, study design, study arms, and analytical methods, all before the data lock/unblinding. In all cases, justification for the changes was documented in the trial protocol or SAP, signed off by the trial biostatistician and principal investigator, and reviewed/approved by an institutional review board, data and safety monitoring board, or sponsor. We recommend that SAP changes can be acceptable up to the time of data lock/unblinding. To maintain full transparency and necessary rigor, clear documentation of such changes should include details, rationale, date(s) such changes were implemented, and evidence of approval by relevant oversight bodies.

Efficacy and safety analysis of Kaiyu Jiangzhuo Tongzhi prescription for the treatment of pre-diabetic overweight/obese patients: a multicentre randomised controlled clinical study protocol and statistical analysis plan

The Chinese Academy of Traditional Chinese Medicine's academician Xiaolin Tong developed the Kaiyu Jiangzhuo Tongzhi prescription (KYJZ) in response to prediabetes's "yu" mechanism. This study plans to thoroughly evaluate the safety and effectiveness of KYJZ in treating prediabetes and preventing diabetes mellitus. This study is a multicenter, randomized, double-blind, placebo-controlled trial in which 598 patients with pre-diabetes were randomly assigned in a 1:1 ratio to either the KYJZ or the placebo group. The primary outcome was to assess the incidence of diabetes at the end of 48 weeks. Secondary outcomes included the rate of normal conversion to glucose tolerance at the end of 48 weeks, indicators of glucose-fat metabolism, body mass index (BMI), waist circumference (WC), and Diabetes Symptom Rating Scale (DSRS), as well as body composition analysis (BCA) and diabetes risk score (DRS). Record all adverse events that occur and analyze the data collected. The results of this study will provide strong evidence for the efficacy and safety of KYJZ in reducing the incidence of diabetes mellitus in overweight/obese patients with prediabetes.

Early In-Bed Cycle Ergometry With Critically Ill, Mechanically Ventilated Patients: Statistical Analysis Plan for CYCLE (Critical Care Cycling to Improve Lower Extremity Strength), an International, Multicenter, Randomized Clinical Trial.

Survivors of critical illness are at risk of developing physical dysfunction following intensive care unit (ICU) discharge. ICU-based rehabilitation interventions, such as early in-bed cycle ergometry, may improve patients' short-term physical function. Before unblinding and trial database lock, we describe a prespecified statistical analysis plan (SAP) for the CYCLE (Critical Care Cycling to Improve Lower Extremity Strength) randomized controlled trial (RCT). CYCLE is a 360-patient, international, multicenter, open-label, parallel-group RCT (1:1 ratio) with blinded primary outcome assessment at 3 days post-ICU discharge. The principal investigator and statisticians of CYCLE prepared this SAP with approval from the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes (including adverse events) and describes the planned primary, secondary, and subgroup analyses. The primary outcome of the CYCLE trial is the Physical Function Intensive Care Unit Test-scored (PFIT-s) at 3 days post-ICU discharge. The PFIT-s is a reliable and valid performance-based measure. We plan to use a frequentist statistical framework for all analyses. We will conduct a linear regression to evaluate the primary outcome, incorporating randomization as an independent variable and adjusting for age (≥65 years versus <65 years) and center. The regression results will be reported as mean differences in PFIT-s scores with corresponding 95% CIs and P values. We consider a 1-point difference in PFIT-s score to be clinically important. Additionally, we plan to conduct 3 subgroup analyses: age (≥65 years versus <65 years), frailty (Baseline Clinical Frailty Scale ≥5 versus <5), and sex (male versus female). CYCLE was funded in 2017, and enrollment was completed in May 2023. Data analyses are complete, and the first results were submitted for publication in 2024. We developed and present an SAP for the CYCLE RCT and will adhere to it for all analyses. This study will add to the growing body of evidence evaluating the efficacy and safety of ICU-based rehabilitation interventions. ClinicalTrials.gov NCT03471247; https://clinicaltrials.gov/ct2/show/NCT03471247 and NCT02377830; https://clinicaltrials.gov/ct2/show/NCT02377830. RR1-10.2196/54451.

The Oncology QCARD Initiative: Fostering efficient evaluation of initial real-world data proposals.

The oncology quality, characterization, and assessment of real-world data (Oncology QCARD) Initiative was formed to develop a set of minimum study design and data elements needed to evaluate the fitness of the real-world data (RWD) source(s) proposed in an initial study concept as part of early interaction with scientific reviewers. A multidisciplinary executive committee (EC) was established to guide the Oncology QCARD Initiative. The EC conducted a landscape review of published literature, guidances, and guidelines to evaluate relevant dimensions of data quality measurement. Guided by the review and informed by expert feedback, the Oncology QCARD Initial Protocol Characterization (IPC) provides a summary of minimum elements needed to adequately describe an initial clinical study concept that involves RWD and is intended to support decision-making. Fit-for-use data and fit-for-purpose design emerged as themes from the landscape analysis. Data that are fit-for-use are both relevant (sufficiently capturing exposure, outcomes, and covariates) and reliable (understanding data accrual and quality control and whether the data represent the underlying concepts they are intended to represent) to answer a specific research question. A fit-for-purpose design takes appropriate steps to ensure internal and external validity and allows for transparency in reporting. The QCARD-IPC focuses on high-level characteristics of RWD sources and study design domains including data temporality, population, medical product exposure, comparators, and covariates, endpoints, statistical analysis, and data quality assurance plans. Evaluation of studies including RWD requires understanding the data source, study design, and potential biases to preliminarily evaluate whether selected RWD are fit-for-use for the research question. The Oncology QCARD-IPC provides a structured, transparent approach to facilitate early review and enhanced communication between study sponsors and scientific reviewers of initial study proposals including RWD.

Africa Health Research Institute (AHRI) Household Contact study: a study protocol, statistical analysis and modelling plan

Household case-contact studies are an established method to estimate the relative infectiousness of people with pulmonary tuberculosis. Testing of child household contacts with a QuantiFERON TB Gold plus (QFT) assay provides a proxy measure of M. tuberculosis infection in exposed household members. This study aims to generate data about the effect of antiretroviral treatment (ART) and of tuberculosis symptoms on risk of intra-household M. tuberculosis transmission to children and investigate the conditions under which symptom-agnostic screening should be considered, which could provide evidence to support a paradigm shift in tuberculosis screening strategy. Index people diagnosed with bacteriologically-confirmed pulmonary tuberculosis who have been identified by routine health services and starting tuberculosis treatment at one of the 12 health facilities serving the population of the Africa Health Research Institute health and demographic surveillance area will be eligible for recruitment. For each consenting index participant, we will enroll all household members aged 2-14 years who will undergo a symptom screen and provide a blood sample for a QFT and HIV test. We will compare the proportion of child contacts who are QFT-positive in households of (i) index adults who are living with HIV and taking ART vs not taking ART and (ii) index adults engaged in ART care who report no symptoms vs those who report symptoms. We will use a novel mathematical model, incorporating new insights into TB natural history and transmission, to determine the circumstances under which screening for TB, regardless of reported symptoms, would have most impact on tuberculosis incidence and mortality, and explore comparative cost-effectiveness of interventions along the diagnostic pathway at different levels of the health system. Estimates of relative risk of intra-household M. tuberculosis transmission, combined with healthcare utilisation and cost data, will allow us to generate mathematical model estimates of the potential epidemiological impact and relative cost-effectiveness of different approaches to tuberculosis case-finding including symptom-agnostic tuberculosis screening at different levels of the health system.

Statistical analysis plan for the Petal trial: the effects of parental touch on relieving acute procedural pain in neonates

Background Infants undergo multiple clinically-required painful procedures during their time in hospital, and there is an increasing desire from both parents and clinical staff to have parents directly involved in their newborn’s pain relief. To avoid biases due to selective analysis and reporting, a clinical trial’s statistical analysis plan (SAP) should be finalised and registered prior to dataset lock and unblinding. Here, we outline the SAP for the Petal trial, which was registered on the ISRCTN registry prior to dataset lock and unblinding. Methods The Petal trial is a multicentre, individually randomised, parallel-group interventional superiority trial. The study involves in-patient neonates born at or after 35+0 weeks gestation with a postnatal age of ≤7 days, in two hospital research sites (John Radcliffe Hospital, Oxford, UK; Royal Devon and Exeter Hospital, Exeter, UK). The primary objective is to investigate the potential efficacy of a non-pharmacological parent-led stroking intervention on reducing the magnitude of neonates’ noxious stimulus-evoked brain activity. The primary outcome is the neonate’s brain activity recorded using electroencephalography (EEG) in response to a heel lance blood sampling procedure. Secondary outcomes include neonatal clinical pain scores and tachycardia, and parental anxiety. The study hypothesis is neonates’ pain responses and parents’ anxiety scores are lower in the intervention group. Randomisation will be via a minimisation algorithm to maintain balance in five prognostic factors. Conclusions Paediatric pain trials have been highlighted by regulatory bodies as an important and challenging topic, with interest increasing in brain imaging outcomes. The Petal trial, to which this SAP relates, is part of a larger effort of establishing a brain-based EEG outcome measure of infant pain for use in clinical trials. This SAP is thus likely to be of interest to those in academia, pharmaceutical companies, and regulatory bodies. Trial registration ClinicalTrials.gov: NCT04901611, 25/05/2021; ISRCTN: ISRCTN14135962, 23/08/2021).

Do summaries of evidence enable informed decision-making about COVID-19 and influenza vaccination equitably across more and less disadvantaged groups? Study protocol for a multi-centre cluster randomised controlled trial of 'fact boxes' in health and social care in Germany.

Evidence summaries on the benefits and harms of treatment options support informed decisions under controlled conditions. However, few studies have investigated how such formats support decision-making across different social groups. There is a risk that only disadvantaged people will be able to make informed health decisions-possibly increasing the health equity gap. It is also unclear whether they support decision-making in the field at all. The aim of our study is to assess whether evidence summaries based on the fact box format can help people from different social groups make informed decisions about COVID-19 and influenza vaccinations, and thus reduce inequity in health communication. In a multi-centre, cluster-randomised, controlled trial, health educators from usual care and outreach work in Germany will be randomised in a 1:1 ratio to provide either usual health communication plus an evidence summary ('fact box') or usual health communication. Health educators provide a flyer about COVID-19 or influenza vaccination which contains a link to an online study either with (intervention) or without (control) fact box on the reverse side. Flyer and online study will be available in Arabic, German, Turkish and Russian language. The primary outcome is informed vaccination intention, based on vaccination knowledge, attitudes, intentions and behaviour. Secondary outcomes include risk perception, decisional conflict and shared decision-making. We will use linear mixed models to analyse the influence of both individual (eg, education status) and cluster level factors and account for the expected cluster variability in realising usual health communication or the intervention. The statistical analysis plan includes the selection of appropriate measures of effect size and power calculation, assuming a sample size of 800 patients. The trial has been approved by the Ethics Committee of the University of Potsdam, Germany (application numbers: 34/2021 and 57/2022).Results will be disseminated through peer-reviewed journals, conferences and to relevant stakeholders. Version 6 (4 October 2024); Preprint available on Research Square: https://doi.org/10.21203/rs.3.rs-3401234/v3 TRIAL REGISTRATION NUMBER: NCT06076421.

Statistical analysis plan for the SOLUTIONS randomised controlled trial with internal pilot: Solution Focused Brief Therapy (SFBT) in 10–17 year olds presenting at police custody

BackgroundWithin England, children and young people entering police custody are referred to Liaison and Diversion (L&D) teams. These teams liaise with healthcare and other support services aiming to divert children and young people away from the criminal justice system. Although targeted psychological interventions are not typically offered to children and young people by L&D teams, evidence suggests that Solution Focused Brief Therapy (SFBT) leads to a reduction in internalising and externalising behaviour problems.MethodsA two-arm individually randomised controlled trial (RCT) with internal pilot and process evaluation will be conducted with approximately 448 children and young people aged 10–17 years presenting at police custody suites who are referred to the L&D team or recruited via online routes if they have previously presented at any police custody suite in England. The primary outcome is the Self-Report Delinquency Measure (SRDM) at 6 months post-randomisation. Analyses will be performed using intention-to-treat.ResultsThe statistical analysis plan (SAP) for the trial is described. The plan details of analyses to be undertaken which will be reported in the primary and any secondary publications. The plan was developed and published prior to locking our database and unblinding to treatment allocation.DiscussionThis RCT will evaluate the effectiveness of SFBT in reducing offending behaviours in CYP presenting at police custody suites including testing of moderating factors and sensitivity of the primary analyses.Trial registrationClinicalTrials.gov ISRCTN14195235. Registered on June 16, 2023.

Recognizing Statistical Problems in Reports of Clinical Trials: A Readers' Aid. Part 33 of a Series on Evaluation of Scientific Publications.

Readers of clinical trial reports should be able to critically evaluate the design, results, and conclusions of the trial. There are internationally accepted guidelines that define methodological standards for trial planning, statistical methods, and the display and interpretation of the results. Publications may nonetheless contain erroneous findings and interpretations. Statistical errors can arise in the planning of the trial, the analysis and display of the results, as well as in the interpretation of p-values and treatment effects in experimental and observational clinical trials. A useful aid for readers of medical publications should include a description of the potential statistical problems without complex theoretical background information. With this aim, we discuss certain major types of statistical error that the reader should be familiar with in order to be able to interpret the conclusions of these publications more easily. Statistical errors can already arise at an early stage through the choice of the wrong question to be addressed or the wrong population to be analyzed; such errors will inevitably have consequences. Before the start of any clinical trial, a primary endpoint must be defined, the sample size must be calculated, and the trial must be appropriately registered (among other requirements). With regard to the analysis, readers should for example take into account whether a statistical analysis plan with an intention-to-treat analysis existed for the study in question. They must be able to recognize erroneous methods of displaying and comparing data, confounding, as well as incorrect interpretations of p-values, and should take these problems into account when interpreting the findings. The problem of invalid causal inferences is not restricted to observational studies. Statistical errors do, indeed, arise. They should be detected as early as possible in various test instances. Nonetheless, readers should be able to judge independently whether the published clinical trial reflects meticulous and correct trial planning, appropriate display of the trial's results, and a proper, reasoned interpretation of the findings. The published checklists are a good aid for this purpose.

The Chronic Progressive Repeated Measures (CPRM) Model for Clinical Trials Comparing Change Over Time in Quantitative Trait Outcomes

Repeated measures analysis is a common analysis plan for clinical trials comparing change over time in quantitative trait outcomes in treatment versus control. Mixed model for repeated measures (MMRM) assuming an unstructured covariance of repeated measures is the default statistical analysis plan, with alternative covariance structures specified in the event that the MMRM model with unstructured covariance does not converge. We here describe a parsimonious covariance structure for repeated measures analysis that is specifically appropriate for longitudinal repeated measures of chronic progressive conditions. This model has the parsimonious features of the mixed effects model with random slopes and intercepts, but without restricting the repeated measure means to be linear with time. We demonstrate with data from completed trials that this pattern of longitudinal trajectories spreading apart over time is typical of Alzheimer’s disease. We further demonstrate that alternative covariance structures typically specified in statistical analysis plans using MMRM perform poorly for chronic progressive conditions, with the compound symmetry model being anticonservative, and the autoregressive model being poorly powered. Finally, we derive power calculation formulas for the chronic progressive repeated measures model that have the advantage of being independent of the design of the pilot studies informing the power calculations. When data follow the pattern of a chronic progressive condition. These power formulas are also appropriate for sizing clinical trials using MMRM analysis with unstructured covariance of repeated measures.