Surrogate Marker Assessment Using Mediation and Instrumental Variable Analyses in a Case-Cohort Design

The identification of surrogate markers for gold standard outcomes in clinical trials enables future cost-effective trials that target the identified markers. Due to resource limitations, these surrogate markers may be collected only for cases and for a subset of the trial cohort, giving rise to what is termed the case-cohort design. Motivated by a COVID-19 vaccine trial, we propose methods of assessing the surrogate markers for a time-to-event outcome in a case-cohort design by using mediation and instrumental variable (IV) analyses. In the mediation analysis we decomposed the vaccine effect on COVID-19 risk into an indirect effect (the effect mediated through the surrogate marker such as neutralizing antibodies) and a direct effect (the effect not mediated by the marker), and we propose that the mediation proportions are surrogacy indices. In the IV analysis we aimed to quantify the causal effect of the surrogate marker on disease risk in the presence of surrogatedisease confounding which is unavoidable even in randomized trials. We employed weighted estimating equations derived from nonparametric maximum likelihood estimators (NPMLEs) under semiparametric probit models for the time-to-disease outcome. We plugged in the weighted NPMLEs to construct estimators for the aforementioned causal effects and surrogacy indices, and we determined the asymptotic properties of the proposed estimators. Finite sample performance was evaluated in numerical simulations. Applying the proposed mediation and IV analyses to a mock COVID-19 vaccine trial data, we found that 84.2% of the vaccine efficacy was mediated by 50% pseudovirus neutralizing antibody and that neutralizing antibodies had significant protective effects for COVID-19 risk.

Mediation analysis with multiple mediators under unmeasured mediator-outcome confounding.

It is often of interest in the health and social sciences to investigate the joint mediation effects of multiple post-exposure mediating variables. Identification of such joint mediation effects generally require no unmeasured confounding of the outcome with respect to the whole set of mediators. As the number of mediators under consideration grows, this key assumption is likely to be violated as it is often infeasible to intervene on any of the mediators. In this article, we develop a simple two-step method of moments estimation procedure to assess mediation with multiple mediators simultaneously in the presence of potential unmeasured mediator-outcome confounding. Our identification result leverages heterogeneity of the population exposure effect on the mediators, which is plausible under a variety of empirical settings. The proposed estimators are illustrated through both simulations and an application to evaluate the mediating effects of post-traumatic stress disorder symptoms in the association between self-efficacy and fatigue among health care workers during the COVID-19 outbreak.

Pre-infection antiviral innate immunity contributes to sex differences in SARS-CoV-2 infection.

Male sex is a major risk factor for SARS-CoV-2 infection severity. To understand the basis for this sex difference, we studied SARS-CoV-2 infection in a young adult cohort of United States Marine recruits. Among 2,641 male and 244 female unvaccinated and seronegative recruits studied longitudinally, SARS-CoV-2 infections occurred in 1,033 males and 137 females. We identified sex differences in symptoms, viral load, blood transcriptome, RNA splicing, and proteomic signatures. Females had higher pre-infection expression of antiviral interferon-stimulated gene (ISG) programs. Causal mediation analysis implicated ISG differences in number of symptoms, levels of ISGs, and differential splicing of CD45 lymphocyte phosphatase during infection. Our results indicate that the antiviral innate immunity set point causally contributes to sex differences in response to SARS-CoV-2 infection. A record of this paper's transparent peer review process is included in the supplemental information.

Socioeconomic Status, Peer Social Capital, and Quality of Life of High School Students During COVID-19: A Mediation Analysis.

This paper investigates how peer social capital mediates associations between socioeconomic status and quality of life among adolescents during the COVID-19 pandemic. Using survey data and school administration records collected at a high school (N = 1,736) in a coastal province in China, the results demonstrate that adolescents' socioeconomic status is associated strongly with their quality of life. When students were learning at home during COVID-19 school closures, peer social capital exerted a mediating effect on the association between socioeconomic status and quality of life. Most importantly, while peer social capital rooted in the real world seemed to be related positively to higher quality of life, peer social capital in the virtual world led to lower quality of life. These findings suggest that peer social capital might manifest different impact mechanisms for adolescents during the pandemic. Theoretical contributions and policy implications are discussed in this paper.

Role of medical comorbidity in the association between psychiatric disorders and mortality among patients with COVID-19.

We examined whether excess chronic medical comorbidity mediated excess COVID-19 inpatient mortality among people with mental disorders in the early phase of the pandemic, a question with important implications for public health and clinical decision-making. Using records of 2599 COVID-19 hospitalized patients, we conducted a formal causal mediation analysis to estimate the extent to which chronic comorbidity mediates the association between mental disorders and COVID-19 mortality. The Odds Ratio (95% CI) for Natural Indirect Effect and Controlled Direct Effect were 1.07(1.02, 1.14) and 1.40 (1.00, 1.95), respectively, suggesting that a large proportion of excess COVID-19 mortality among people with mental disorders may be explained by factors other than comorbidity.