Finding a Needle in the Haystack: Design and Implementation of a Digital Site-less Clinical Study of Serial Rapid Antigen Testing to Identify Asymptomatic SARS-CoV-2 Infection

Abstract

Background: Over-the-counter rapid antigen tests for SARS-CoV-2 with an Emergency Use Authorization (EUA) in the United States generally include a condition of authorization to evaluate the test's performance in asymptomatic individuals when used serially. A goal of this study was to investigate the performance of SARS-CoV-2 antigen serial testing and generate data to support regulatory decisions. Objective: To describe a novel study design to evaluate serial use of rapid antigen tests in detecting SARS-CoV-2 virus among asymptomatic individuals. Design: Prospective cohort study using a decentralized approach. Eligible participants from across the U.S. could enroll and complete this study from their home environment through a study app. Participant enrollment was prioritized based on regional 7-day case rates, participants' vaccination status, and sociodemographic characteristics prior to enrollment. Prioritization criteria were adjusted on a daily or weekly basis. Enrolled participants were mailed rapid antigen tests and molecular comparator collection kits and asked to test every 48 hours for 15 days. Three companies' rapid antigen tests were used in the study; assignment of participant to a test was criteria-based and non-random, precluding head-to-head comparison between the tests. Participants: Mainland United States residents over 2 years old with no reported COVID-19 symptoms in the 14 days prior to study enrollment. Main Measures: Participant demographics, COVID-19 vaccination status, and geographic distribution were used to understand the impact of the site-less recruitment and enrollment strategy. Key Results: A total of 7,361 participants enrolled in the study between October 18, 2021 and February 15, 2022. Throughout the study, 369 participants tested positive for SARS-CoV-2, including 167 who were asymptomatic and tested negative on SARS-CoV-2 molecular assays to start the study. This exceeded the initial enrollment goals of 60 positive participants. We enrolled participants from 44 of the 48 mainland U.S. states, and geographic distribution of participants shifted in accordance with the changing COVID-19 prevalence nationwide. Conclusions: The novel, digital site-less approach employed in the 'Test Us At Home' study enabled rapid, efficient, and rigorous evaluation of rapid diagnostics for COVID-19, and can be adapted across research disciplines to optimize study enrollment and accessibility.

Competing Interest Statement

VK is principal, and TS, SS, CN, ES, and EH are employees of the health care technology company CareEvolution, which was contracted to configure the smartphone study app, provide operational and logistical support, and collaborate on overall research approach. LS and LR are employees of Quest Diagnostics LLC, which was contracted to provide direct-to-consumer kits, logistical support for nationwide RT-PCR testing, and operational support for producing molecular testing results. DDM reports consulting and research grants from Bristol-Myers Squibb and Pfizer, consulting and research support from Fitbit, consulting, and research support from Flexcon, research grant from Boehringer Ingelheim, consulting from Avania, non-financial research support from Apple Computer, consulting/other support from Heart Rhythm Society. YCM has received tests from Quanterix, Becton-Dickinson, Ceres, and Hologic for research-related purposes, consults for Abbott on subjects unrelated to SARS-CoV-2, and receives funding support to Johns Hopkins University from miDiagnostics. AS receives non-financial support from CareEvolution for collaborative research activities.

Funding Statement

This study was funded by the NIH RADx Tech program under 3U54HL143541-02S2 and NIH CTSA grant UL1TR001453. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Institute of Biomedical Imaging and Bioengineering; the National Heart, Lung, and Blood Institute; the National Institutes of Health, or the U.S. Department of Health and Human Services. Salary support from the National Institutes of Health U54HL143541, R01HL141434, R01HL137794, R61HL158541, R01HL137734, U01HL146382 (AS, DDM), U54EB007958-13 (YCM, MLR), AI272201400007C, UM1AI068613 (YCM).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The IRB of WIRB-Copernicus Group gave ethical approval for this work (20214875).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

Data Availability

All data produced in the present study are available upon reasonable request to the authors.

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