Demystifying estimands in cluster-randomised trials.

Estimands can help clarify the interpretation of treatment effects and ensure that estimators are aligned with the study's objectives. Cluster-randomised trials require additional attributes to be defined within the estimand compared to individually randomised trials, including whether treatment effects are marginal or cluster-specific, and whether they are participant- or cluster-average. In this paper, we provide formal definitions of estimands encompassing both these attributes using potential outcomes notation and describe differences between them. We then provide an overview of estimators for each estimand, describe their assumptions, and show consistency (i.e. asymptotically unbiased estimation) for a series of analyses based on cluster-level summaries. Then, through a re-analysis of a published cluster-randomised trial, we demonstrate that the choice of both estimand and estimator can affect interpretation. For instance, the estimated odds ratio ranged from 1.38 (p = 0.17) to 1.83 (p = 0.03) depending on the target estimand, and for some estimands, the choice of estimator affected the conclusions by leading to smaller treatment effect estimates. We conclude that careful specification of the estimand, along with an appropriate choice of estimator, is essential to ensuring that cluster-randomised trials address the right question.

Assessing treatment effect heterogeneity in the presence of missing effect modifier data in cluster-randomized trials.

Understanding whether and how treatment effects vary across subgroups is crucial to inform clinical practice and recommendations. Accordingly, the assessment of heterogeneous treatment effects based on pre-specified potential effect modifiers has become a common goal in modern randomized trials. However, when one or more potential effect modifiers are missing, complete-case analysis may lead to bias and under-coverage. While statistical methods for handling missing data have been proposed and compared for individually randomized trials with missing effect modifier data, few guidelines exist for the cluster-randomized setting, where intracluster correlations in the effect modifiers, outcomes, or even missingness mechanisms may introduce further threats to accurate assessment of heterogeneous treatment effect. In this article, the performance of several missing data methods are compared through a simulation study of cluster-randomized trials with continuous outcome and missing binary effect modifier data, and further illustrated using real data from the Work, Family, and Health Study. Our results suggest that multilevel multiple imputation and Bayesian multilevel multiple imputation have better performance than other available methods, and that Bayesian multilevel multiple imputation has lower bias and closer to nominal coverage than standard multilevel multiple imputation when there are model specification or compatibility issues.

Acceptability of a Randomized Trial of Anti-depressant Medication or Interpersonal Therapy for Treatment of Perinatal Depression in Women with HIV.

Postpartum depression (PPD) affects nearly 20% of postpartum women in Sub-Saharan Africa (SSA), where HIV prevalence is high. Depression is associated with worse HIV outcomes in non-pregnant adults and mental health disorders may worsen HIV outcomes for postpartum women and their infants. PPD is effectively treated with psychosocial or pharmacologic interventions; however, few studies have evaluated the acceptability of treatment modalities in SSA. We analyzed interviews with 23 postpartum women with HIV to assess the acceptability of two depression treatments provided in the context of a randomized trial. Most participants expressed acceptability of treatment randomization and study visit procedures. Participants shared perceptions of high treatment efficacy of their assigned intervention. They reported ongoing HIV and mental health stigma in their communities and emphasized the importance of social support from clinic staff. Our findings suggest a full-scale trial of PPD treatment will be acceptable among women with HIV in Zambia.

Accuracy of Expected Symptoms and Subsequent Quality of Life Measures Among Adults With COPD.

Importance: Patients' expectations for future health guide their decisions and enable them to prepare, adapt, and cope. However, little is known about how inaccurate expectations may affect patients' illness outcomes. Objective: To assess the association between patients' expectation inaccuracies and health-related quality of life. Design, Setting, and Participants: This cohort study of patients with severe chronic obstructive pulmonary disease (COPD) was conducted from 2017 to 2021, which included a 24-month follow-up period. Eligible participants received outpatient primary care at pulmonary clinics of a single large US health system. Data were analyzed between 2021 and 2023. Exposure: Expectation accuracy, measured by comparing patients' self-reported expectations of their symptom burden with their actual physical and emotional symptoms 3, 12, and 24 months in the future. Main Outcome and Measure: Health-related quality of life, measured by the St George's Respiratory Questionnaire-COPD at 3, 12, and 24 months. Results: A total of 207 participants were included (median age, 65.5 years [range, 42.0-86.0 years]; 120 women [58.0%]; 118 Black [57.0%], 79 White [38.2%]). The consent rate among approached patients was 80.0%. Most patients reported no or only limited discussions of future health and symptom burdens with their clinicians. Across physical and emotional symptoms and all 3 time points, patients' expectations were more optimistic than their experiences. There were no consistent patterns of measured demographic or behavioral characteristics associated with expectation accuracy. Regression models revealed that overoptimistic expectations of future burdens of dyspnea (linear regression estimate, 4.68; 95% CI, 2.68 to 6.68) and negative emotions (linear regression estimate, -3.04; 95% CI, -4.78 to 1.29) were associated with lower health-related quality of life at 3 months after adjustment for baseline health-related quality of life, forced expiratory volume over 1 second, and interval clinical events (P < .001 for both). Similar patterns were observed at 12 months (dyspnea: linear regression estimate, 2.41; 95% CI, 0.45 to 4.37) and 24 months (negative emotions: linear regression estimate, -2.39; 95% CI, -4.67 to 0.12; dyspnea: linear regression estimate, 3.21; 95% CI, 0.82 to 5.60), although there was no statistically significant association between expectation of negative emotions and quality of life at 12 months. Conclusions and Relevance: In this cohort study of patients with COPD, we found that patients are overoptimistic in their expectations about future negative symptom burdens, and such inaccuracies were independently associated with worse well-being over time. Developing and implementing strategies to improve patients' symptom expectations may improve patient-centered outcomes.

Is low-risk status a surrogate outcome in pulmonary arterial hypertension? An analysis of three randomised trials.

BACKGROUND: Targeting short-term improvements in multicomponent risk scores for mortality in patients with pulmonary arterial hypertension (PAH) could result in improved long-term outcomes. We aimed to determine whether PAH risk scores were adequate surrogates for clinical worsening or mortality outcomes in PAH randomised clinical trials (RCTs). METHODS: We performed an individual participant data meta-analysis of RCTs selected from PAH trials provided by the US Food and Drug Administration (FDA). We calculated predicted risk using the COMPERA, COMPERA 2.0, non-invasive FPHR, REVEAL 2.0, and REVEAL Lite 2 risk scores. The primary outcome of interest was time to clinical worsening, a composite endpoint composed of any of the following events: all-cause death, hospitalisation for worsening PAH, lung transplantation, atrial septostomy, discontinuation of study treatment (or study withdrawal) for worsening PAH, initiation of parenteral prostacyclin analogue therapy, or decrease of at least 15% in 6-min walk distance from baseline, combined with either worsening of WHO functional class from baseline or the addition of an approved PAH treatment. The secondary outcome of interest was time to all-cause mortality. We assessed the surrogacy of these risk scores, parameterised as attainment of low-risk status by 16 weeks, for improvement in long-term clinical worsening and survival using mediation and meta-analysis frameworks. FINDINGS: Of 28 trials received from the FDA, three RCTs (AMBITION, GRIPHON, and SERAPHIN; n=2508) had the data necessary to assess long-term surrogacy. The mean age was 49 years (SD 16), 1956 (78%) participants were women, 1704 (68%) were classified as White, and 280 (11%) were Hispanic or Latino. 1388 (55%) of 2503 participants with available data had idiopathic PAH and 776 (31%) of 2503 had PAH associated with connective tissue disease. In a mediation analysis, the proportions of treatment effects explained by attainment of low-risk status ranged only from 7% to 13%. In a meta-analysis of trial-regions, the treatment effects on low-risk status were not predictive of the treatment effects on time to clinical worsening (R2 values 0·01-0·19) nor the treatment effects on time to all-cause mortality (R2 values 0-0·2). A leave-one-out analysis suggested that the use of these risk scores as surrogates might lead to biased inferences regarding the effect of therapies on clinical outcomes in PAH RCTs. Results were similar when using absolute risk scores at 16 weeks as the potential surrogates. INTERPRETATION: Multicomponent risk scores have utility for the prediction of outcomes in patients with PAH. Clinical surrogacy for long-term outcomes cannot be inferred from observational studies of outcomes. Our analyses of three PAH trials with long-term follow-up suggest that further study is necessary before using these or other scores as surrogate outcomes in PAH RCTs or clinical care. FUNDING: Cardiovascular Medical Research and Education Fund, US National Institutes of Health.

Causal Bayesian machine learning to assess treatment effect heterogeneity by dexamethasone dose for patients with COVID-19 and severe hypoxemia.

The currently recommended dose of dexamethasone for patients with severe or critical COVID-19 is 6 mg per day (mg/d) regardless of patient features and variation. However, patients with severe or critical COVID-19 are heterogenous in many ways (e.g., age, weight, comorbidities, disease severity, and immune features). Thus, it is conceivable that a standardized dosing protocol may not be optimal. We assessed treatment effect heterogeneity in the COVID STEROID 2 trial, which compared 6 mg/d to 12 mg/d, using a causal inference framework with Bayesian Additive Regression Trees, a flexible modeling method that detects interactive effects and nonlinear relationships among multiple patient characteristics simultaneously. We found that 12 mg/d of dexamethasone, relative to 6 mg/d, was probably associated with better long-term outcomes (days alive without life support and mortality after 90 days) among the entire trial population (i.e., no signals of harm), and probably more beneficial among those without diabetes mellitus, that were older, were not using IL-6 inhibitors at baseline, weighed less, or had higher level respiratory support at baseline. This adds more evidence supporting the use of 12 mg/d in practice for most patients not receiving other immunosuppressants and that additional study of dosing could potentially optimize clinical outcomes.

A Bayesian Interpretation of a Pediatric Cardiac Arrest Trial (THAPCA-OH).

BACKGROUND: Pediatric out-of-hospital cardiac arrest results in high morbidity and mortality. Currently, there are no recommended therapies beyond supportive care. The THAPCA-OH (Therapeutic Hypothermia after Pediatric Cardiac Arrest Out-of-Hospital) trial compared hypothermia (33.0°C) with normothermia (36.8°C) in 295 children. Good neurobehavioral outcome and survival at 1 year were higher in the hypothermia group (20 vs. 12% and 38 vs. 29%, respectively). These differences did not meet the planned statistical threshold of P75% for all informative prior integrations with the THAPCA-OH results, except those with the most pessimistic priors. CONCLUSIONS: There is a high probability that hypothermia provides a modest benefit in neurobehavioral outcome and survival at 1 year. (ClinicalTrials.gov number, NCT00878644.)

Interpersonal therapy versus antidepressant medication for treatment of postpartum depression and anxiety among women with HIV in Zambia: a randomized feasibility trial.

INTRODUCTION: Postpartum depression (PPD) is a prevalent and debilitating disease that may affect medication adherence and thus maternal health and vertical transmission among women with HIV. We assessed the feasibility of a trial of interpersonal psychotherapy (IPT) versus antidepressant medication (ADM) to treat PPD and/or anxiety among postpartum women with HIV in Lusaka, Zambia. METHODS: Between 29 October 2019 and 8 September 2020, we pre-screened women 6-8 weeks after delivery with the Edinburgh Postnatal Depression Scale (EPDS) and diagnosed PPD or anxiety with the Mini International Neuropsychiatric Interview. Consenting participants were randomized 1:1 to up to 11 sessions of IPT or daily self-administered sertraline and followed for 24 weeks. We assessed EPDS score, Clinical Global Impression-Severity of Illness (CGI-S) and medication side effects at each visit and measured maternal HIV viral load at baseline and final study visit. Retention, visit adherence, change in EPDS, CGI-S and log viral load were compared between groups with t-tests and Wilcoxon signed rank tests; we report mean differences, relative risks and 95% confidence intervals. A participant satisfaction survey assessed trial acceptability. RESULTS: 78/80 (98%) participants were retained at the final study visit. In the context of the COVID-19 pandemic, visit adherence was greater among women allocated to ADM (9.9 visits, SD 2.2) versus IPT (8.9 visits, SD 2.4; p = 0.06). EPDS scores decreased from baseline to final visit overall, though mean change was greater in the IPT group (-13.8 points, SD 4.7) compared to the ADM group (-11.4 points, SD 5.5; p = 0.04). Both groups showed similar changes in mean log viral load from baseline to final study visit (mean difference -0.43, 95% CI -0.32, 1.18; p = 0.48). In the IPT group, viral load decreased significantly from baseline (0.9 log copies/ml, SD 1.7) to final visit (0.2 log copies/ml, SD 0.9; p = 0.01). CONCLUSIONS: This pilot study demonstrates that a trial of two forms of PPD treatment is feasible and acceptable among women with HIV in Zambia. IPT and ADM both improved measures of depression severity; however, a full-scale trial is required to determine whether treatment of PPD and anxiety improves maternal-infant HIV outcomes.

Post-randomization Biomarker Effect Modification Analysis in an HIV Vaccine Clinical Trial.

While the HVTN 505 trial showed no overall efficacy of the tested vaccine to prevent HIV infection over placebo, markers measuring immune response to vaccination were strongly correlated with infection. This finding generated the hypothesis that some marker-defined vaccinated subgroups were partially protected whereas others had their risk increased. This hypothesis can be assessed using the principal stratification framework (Frangakis and Rubin, 2002) for studying treatment effect modification by an intermediate response variable, using methods in the sub-field of principal surrogate (PS) analysis that studies multiple principal strata. Unfortunately, available methods for PS analysis require an augmented study design not available in HVTN 505, and make untestable structural risk assumptions, motivating a need for more robust PS methods. Fortunately, another sub-field of principal stratification, survivor average causal effect (SACE) analysis (Rubin, 2006) - which studies effects in a single principal stratum - provides many methods not requiring an augmented design and making fewer assumptions. We show how, for a binary intermediate response variable, methods developed for SACE analysis can be adapted to PS analysis, providing new and more robust PS methods. Application to HVTN 505 supports that the vaccine partially protected individuals with vaccine-induced T-cells expressing certain combinations of functions.

Antibody Fc effector functions and IgG3 associate with decreased HIV-1 risk.

HVTN 505 is a preventative vaccine efficacy trial testing DNA followed by recombinant adenovirus serotype 5 (rAd5) in circumcised, Ad5-seronegative men and transgendered persons who have sex with men in the United States. Identified immune correlates of lower HIV-1 risk and a virus sieve analysis revealed that, despite lacking overall efficacy, vaccine-elicited responses exerted pressure on infecting HIV-1 viruses. To interrogate the mechanism of the antibody correlate of HIV-1 risk, we examined antigen-specific antibody recruitment of Fcγ receptors (FcγRs), antibody-dependent cellular phagocytosis (ADCP), and the role of anti-envelope (anti-Env) IgG3. In a prespecified immune correlates analysis, antibody-dependent monocyte phagocytosis and antibody binding to FcγRIIa correlated with decreased HIV-1 risk. Follow-up analyses revealed that anti-Env IgG3 breadth correlated with reduced HIV-1 risk, anti-Env IgA negatively modified infection risk by Fc effector functions, and that vaccine recipients with a specific FcγRIIa single-nucleotide polymorphism locus had a stronger correlation with decreased HIV-1 risk when ADCP, Env-FcγRIIa, and IgG3 binding were high. Additionally, FcγRIIa engagement correlated with decreased viral load setpoint in vaccine recipients who acquired HIV-1. These data support a role for vaccine-elicited anti-HIV-1 Env IgG3, antibody engagement of FcRs, and phagocytosis as potential mechanisms for HIV-1 prevention.

High School Physical Activity and Nutrition Policy: Summarizing Changes Over Time Using Latent Class Analysis.

INTRODUCTION: High school physical activity and nutrition policies can substantially affect student behavior and outcomes. Although public health officials and legislators have advocated for policy improvements, the extent to which policies have changed at local levels is not well understood. This study identifies latent classes of physical activity and nutrition policy environments and explores changes in prevalence of these classes from 2000 to 2016. METHODS: Data from the School Health Policies and Practices Study, a repeated cross-sectional survey from the Centers for Disease Control and Prevention administered at the school district level in 2000, 2006, 2012, and 2016, were analyzed in 2018. Using latent class analysis, policy environment subgroups were identified, described, and then dichotomized based on satisfaction in meeting recommendations. Associations of latent classes with year and urbanicity were evaluated using logistic regression. RESULTS: Five latent classes were identified each for physical activity and nutrition policy environments, all with distinct characteristics. Physical activity policies improved from 2000 to 2006 (p<0.001) and then plateaued until 2016, whereas nutrition policies improved consistently from 2000 to 2016 (p<0.001, p=0.011, p<0.001). Though significant disparities between urban and rural school districts were found, these disparities narrowed during the studied years, particularly for physical activity policies. CONCLUSIONS: The estimated proportion of school districts with satisfactory physical activity and nutrition policy environments increased from 2000 to 2016, possibly because of legislative and policy advocacy efforts. However, many areas for improvement remain. Unsatisfactory latent classes that remained prevalent though 2016 may highlight policy domains that should be targeted by future interventions or subject to further research.