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Causal mediation analysis aims to characterize an exposure's effect on an outcome and quantify the indirect effect that acts through a given mediator or a group of mediators of interest. With the increasing availability of measurements on a large number of potential mediators, like the epigenome or the microbiome, new statistical methods are needed to simultaneously accommodate high-dimensional mediators while directly target penalization of the natural indirect effect (NIE) for active mediator identification. Here, we develop two novel prior models for identification of active mediators in high-dimensional mediation analysis through penalizing NIEs in a Bayesian paradigm. Both methods specify a joint prior distribution on the exposure-mediator effect and mediator-outcome effect with either (a) a four-component Gaussian mixture prior or (b) a product threshold Gaussian prior. By jointly modelling the two parameters that contribute to the NIE, the proposed methods enable penalization on their product in a targeted way. Resultant inference can take into account the four-component composite structure underlying the NIE. We show through simulations that the proposed methods improve both selection and estimation accuracy compared to other competing methods. We applied our methods for an in-depth analysis of two ongoing epidemiologic studies: the Multi-Ethnic Study of Atherosclerosis (MESA)more »and the LIFECODES birth cohort. The identified active mediators in both studies reveal important biological pathways for understanding disease mechanisms.

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Susceptible-Exposed-Infected-Removed (SEIR)-type epidemiologic models, modeling unascertained infections latently, can predict unreported cases and deaths assuming perfect testing. We apply a method we developed to account for the high false negative rates of diagnostic RT-PCR tests for detecting an active SARS-CoV-2 infection in a classic SEIR model. The number of unascertained cases and false negatives being unobservable in a real study, population-based serosurveys can help validate model projections. Applying our method to training data from Delhi, India, during March 15–June 30, 2020, we estimate the underreporting factor for cases at 34–53 (deaths: 8–13) on July 10, 2020, largely consistent with the findings of the first round of serosurveys for Delhi (done during June 27–July 10, 2020) with an estimated 22.86% IgG antibody prevalence, yielding estimated underreporting factors of 30–42 for cases. Together, these imply approximately 96–98% cases in Delhi remained unreported (July 10, 2020). Updated calculations using training data during March 15-December 31, 2020 yield estimated underreporting factor for cases at 13–22 (deaths: 3–7) on January 23, 2021, which are again consistent with the latest (fifth) round of serosurveys for Delhi (done during January 15–23, 2021) with an estimated 56.13% IgG antibody prevalence, yielding an estimated range for the underreportingmore »factor for cases at 17–21. Together, these updated estimates imply approximately 92–96% cases in Delhi remained unreported (January 23, 2021). Such model-based estimates, updated with latest data, provide a viable alternative to repeated resource-intensive serosurveys for tracking unreported cases and deaths and gauging the true extent of the pandemic.

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With only 536 COVID-19 cases and 11 fatalities, India took the historic decision of a 21-day national lockdown on March 25, 2020. The lockdown was first extended to May 3 soon after the analysis of this article was completed, and then to May 18 while this article was being revised. In this article, we use a Bayesian extension of the susceptible-infected-removed (eSIR) model designed for intervention forecasting to study the short- and long-term impact of an initial 21-day lockdown on the total number of COVID-19 infections in India compared to other, less severe nonpharmaceutical interventions. We compare effects of hypothetical durations of lockdown on reducing the number of active and new infections. We find that the lockdown, if implemented correctly, can reduce the total number of cases in the short term, and buy India invaluable time to prepare its health care and disease-monitoring system. Our analysis shows we need to have some measures of suppression in place after the lockdown for increased benefit (as measured by reduction in the number of cases). A longer lockdown from 42–56 days is preferable to substantially ‘flatten the curve’ when compared to 21–28 days of lockdown. Our models focus solely on projecting the numbermore »of COVID-19 infections and thus inform policymakers about one aspect of this multifaceted decision-making problem. We conclude with a discussion on the pivotal role of increased testing, reliable and transparent data, proper uncertainty quantification, accurate interpretation of forecasting models, reproducible data science methods, and tools that can enable data-driven policymaking during a pandemic. Our software products are available at covind19.org.« less