Using Quantitative Bias Analysis to Adjust for Misclassification of COVID-19 Outcomes: An Applied Example of Inhaled Corticosteroids and COVID-19 Outcomes

Overview

Journal Pharmacoepidemiol Drug Saf

Publisher Wiley

Specialties Pharmacology
Public Health

Date 2025 Jan 8

PMID 39776023

Authors

Marleen Bokern

Christopher T Rentsch

Jennifer K Quint

Jacob Hunnicutt

Ian Douglas

Anna Schultze

Affiliations

Soon will be listed here.

Abstract

Background: During the pandemic, there was concern that underascertainment of COVID-19 outcomes may impact treatment effect estimation in pharmacoepidemiologic studies. We assessed the impact of outcome misclassification on the association between inhaled corticosteroids (ICS) and COVID-19 hospitalisation and death in the United Kingdom during the first pandemic wave using probabilistic bias analysis (PBA).

Methods: Using data from the Clinical Practice Research Datalink Aurum, we defined a cohort with chronic obstructive pulmonary disease (COPD) on 1 March 2020. We compared the risk of COVID-19 hospitalisation and death among users of ICS/long-acting β-agonist (LABA) and users of LABA/LAMA using inverse probability of treatment weighted (IPTW) logistic regression. We used PBA to assess the impact of non-differential outcome misclassification. We assigned beta distributions to sensitivity and specificity and sampled from these 100 000 times for summary-level and 10 000 times for record-level PBA. Using these values, we simulated outcomes and applied IPTW logistic regression to adjust for confounding and misclassification. Sensitivity analyses excluded ICS + LABA + LAMA (triple therapy) users.

Results: Among 161 411 patients with COPD, ICS users had increased odds of COVID-19 hospitalisations and death compared with LABA/LAMA users (OR for COVID-19 hospitalisation 1.59 (95% CI 1.31-1.92); OR for COVID-19 death 1.63 (95% CI 1.26-2.11)). After IPTW and exclusion of people using triple therapy, ORs moved towards the null. All implementations of QBA, both record- and summary-level PBA, modestly shifted the ORs away from the null and increased uncertainty.

Conclusions: We observed increased risks of COVID-19 hospitalisation and death among ICS users compared to LABA/LAMA users. Outcome misclassification was unlikely to change the conclusions of the study, but confounding by indication remains a concern.

References

Yu L, Bafadhel M, Dorward J, Hayward G, Saville B, Gbinigie O . Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021; 398(10303):843-855. PMC: 8354567. DOI: 10.1016/S0140-6736(21)01744-X. View

Schultze A, Walker A, Mackenna B, Morton C, Bhaskaran K, Brown J . Risk of COVID-19-related death among patients with chronic obstructive pulmonary disease or asthma prescribed inhaled corticosteroids: an observational cohort study using the OpenSAFELY platform. Lancet Respir Med. 2020; 8(11):1106-1120. PMC: 7515601. DOI: 10.1016/S2213-2600(20)30415-X. View

Husby A, Pottegard A, Hviid A . Association between inhaled corticosteroid use and COVID-19 outcomes. Pharmacoepidemiol Drug Saf. 2021; 30(11):1486-1492. PMC: 8441753. DOI: 10.1002/pds.5345. View

Frazer J, Frazer G . Analysis of primary care prescription trends in England during the COVID-19 pandemic compared against a predictive model. Fam Med Community Health. 2021; 9(3). PMC: 8338320. DOI: 10.1136/fmch-2021-001143. View

Schneeweiss S, Rassen J, Brown J, Rothman K, Happe L, Arlett P . Graphical Depiction of Longitudinal Study Designs in Health Care Databases. Ann Intern Med. 2019; 170(6):398-406. DOI: 10.7326/M18-3079. View

Jamilloux Y, Henry T, Belot A, Viel S, Fauter M, El Jammal T . Should we stimulate or suppress immune responses in COVID-19? Cytokine and anti-cytokine interventions. Autoimmun Rev. 2020; 19(7):102567. PMC: 7196557. DOI: 10.1016/j.autrev.2020.102567. View

Boulware D, Lindsell C, Stewart T, Hernandez A, Collins S, McCarthy M . Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19. N Engl J Med. 2023; 389(12):1085-1095. PMC: 10597427. DOI: 10.1056/NEJMoa2209421. View

Rothnie K, Mullerova H, Hurst J, Smeeth L, Davis K, Thomas S . Validation of the Recording of Acute Exacerbations of COPD in UK Primary Care Electronic Healthcare Records. PLoS One. 2016; 11(3):e0151357. PMC: 4784784. DOI: 10.1371/journal.pone.0151357. View

Halpin D, Faner R, Sibila O, Badia J, Agusti A . Do chronic respiratory diseases or their treatment affect the risk of SARS-CoV-2 infection?. Lancet Respir Med. 2020; 8(5):436-438. PMC: 7270536. DOI: 10.1016/S2213-2600(20)30167-3. View

10.

Hunnicutt J, Ulbricht C, Chrysanthopoulou S, Lapane K . Probabilistic bias analysis in pharmacoepidemiology and comparative effectiveness research: a systematic review. Pharmacoepidemiol Drug Saf. 2016; 25(12):1343-1353. PMC: 5272921. DOI: 10.1002/pds.4076. View

11.

Wolf A, Dedman D, Campbell J, Booth H, Lunn D, Chapman J . Data resource profile: Clinical Practice Research Datalink (CPRD) Aurum. Int J Epidemiol. 2019; 48(6):1740-1740g. PMC: 6929522. DOI: 10.1093/ije/dyz034. View

12.

Choi J, Jung S, Yoon U, You S, Kim M, Baek M . Inhaled Corticosteroids and COVID-19 Risk and Mortality: A Nationwide Cohort Study. J Clin Med. 2020; 9(11). PMC: 7690894. DOI: 10.3390/jcm9113406. View

13.

Wu G, DSouza A, Quan H, Southern D, Youngson E, Williamson T . Validity of ICD-10 codes for COVID-19 patients with hospital admissions or ED visits in Canada: a retrospective cohort study. BMJ Open. 2022; 12(1):e057838. PMC: 8787827. DOI: 10.1136/bmjopen-2021-057838. View

14.

Kadri S, Gundrum J, Warner S, Cao Z, Babiker A, Klompas M . Uptake and Accuracy of the Diagnosis Code for COVID-19 Among US Hospitalizations. JAMA. 2020; 324(24):2553-2554. PMC: 7756233. DOI: 10.1001/jama.2020.20323. View

15.

Kung S, Doppen M, Black M, Braithwaite I, Kearns C, Weatherall M . Underestimation of COVID-19 mortality during the pandemic. ERJ Open Res. 2021; 7(1). PMC: 7734715. DOI: 10.1183/23120541.00766-2020. View

16.

Aveyard P, Gao M, Lindson N, Hartmann-Boyce J, Watkinson P, Young D . Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study. Lancet Respir Med. 2021; 9(8):909-923. PMC: 8016404. DOI: 10.1016/S2213-2600(21)00095-3. View

17.

Garrido M, Kelley A, Paris J, Roza K, Meier D, Morrison R . Methods for constructing and assessing propensity scores. Health Serv Res. 2014; 49(5):1701-20. PMC: 4213057. DOI: 10.1111/1475-6773.12182. View

18.

Quint J, Mullerova H, DiSantostefano R, Forbes H, Eaton S, Hurst J . Validation of chronic obstructive pulmonary disease recording in the Clinical Practice Research Datalink (CPRD-GOLD). BMJ Open. 2014; 4(7):e005540. PMC: 4120321. DOI: 10.1136/bmjopen-2014-005540. View

19.

Ramakrishnan S, Nicolau Jr D, Langford B, Mahdi M, Jeffers H, Mwasuku C . Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021; 9(7):763-772. PMC: 8040526. DOI: 10.1016/S2213-2600(21)00160-0. View

20.

Clemency B, Varughese R, Gonzalez-Rojas Y, Morse C, Phipatanakul W, Koster D . Efficacy of Inhaled Ciclesonide for Outpatient Treatment of Adolescents and Adults With Symptomatic COVID-19: A Randomized Clinical Trial. JAMA Intern Med. 2021; 182(1):42-49. PMC: 8609464. DOI: 10.1001/jamainternmed.2021.6759. View