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Letter to the EditorCOVID-19 Open Access | 10.1172/JCI156711

Concerns about the interpretation of subgroup analysis. Reply.

Shilong Li,1 Pei Wang,2 and Li Li1

1Sema4, Stamford, Connecticut, USA.

2Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Address correspondence to: Li Li, 333 Ludlow Street, Stamford, Connecticut 06902, USA. Phone: 475.333.3720; Email: li.li@sema4.com.

Find articles by Li, S. in: JCI | PubMed | Google Scholar |

1Sema4, Stamford, Connecticut, USA.

2Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Address correspondence to: Li Li, 333 Ludlow Street, Stamford, Connecticut 06902, USA. Phone: 475.333.3720; Email: li.li@sema4.com.

Find articles by Wang, P. in: JCI | PubMed | Google Scholar |

1Sema4, Stamford, Connecticut, USA.

2Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Address correspondence to: Li Li, 333 Ludlow Street, Stamford, Connecticut 06902, USA. Phone: 475.333.3720; Email: li.li@sema4.com.

Find articles by Li, L. in: JCI | PubMed | Google Scholar |

Published December 2, 2021 - More info

Published in Volume 132, Issue 2 on January 18, 2022
J Clin Invest. 2022;132(2):e156711. https://doi.org/10.1172/JCI156711.
© 2022 Li et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 2, 2021 - Version history
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Related articles:

In-hospital use of ACE inhibitors/angiotensin receptor blockers associates with COVID-19 outcomes in African American patients
Shilong Li, … , Eric E. Schadt, Li Li
Shilong Li, … , Eric E. Schadt, Li Li
Clinical Medicine COVID-19

In-hospital use of ACE inhibitors/angiotensin receptor blockers associates with COVID-19 outcomes in African American patients

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Abstract

BACKGROUND The angiotensin-converting enzyme (ACE) D allele is more prevalent among African Americans compared with other races and ethnicities and has previously been associated with severe coronavirus disease 2019 (COVID-19) pathogenesis through excessive ACE1 activity. ACE inhibitors/angiotensin receptor blockers (ACE-I/ARB) may counteract this mechanism, but their association with COVID-19 outcomes has not been specifically tested in the African American population.METHODS We identified 6218 patients who were admitted into Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York City. We evaluated whether the outpatient and in-hospital use of ACE-I/ARB is associated with COVID-19 in-hospital mortality in an African American compared with non–African American population.RESULTS Of the 6218 patients with COVID-19, 1138 (18.3%) were ACE-I/ARB users. In a multivariate logistic regression model, ACE-I/ARB use was independently associated with a reduced risk of in-hospital mortality in the entire population (OR, 0.655; 95% CI, 0.505–0.850; P = 0.001), African American population (OR, 0.44; 95% CI, 0.249–0.779; P = 0.005), and non–African American population (OR, 0.748, 95% CI, 0.553–1.012, P = 0.06). In the African American population, in-hospital use of ACE-I/ARB was associated with improved mortality (OR, 0.378; 95% CI, 0.188–0.766; P = 0.006), whereas outpatient use was not (OR, 0.889; 95% CI, 0.375–2.158; P = 0.812). When analyzing each medication class separately, ARB in-hospital use was significantly associated with reduced in-hospital mortality in the African American population (OR, 0.196; 95% CI, 0.074–0.516; P = 0.001), whereas ACE-I use was not associated with impact on mortality in any population.CONCLUSION In-hospital use of ARB was associated with a significant reduction in in-hospital mortality among COVID-19–positive African American patients.FUNDING None.

Authors

Shilong Li, Rangaprasad Sarangarajan, Tomi Jun, Yu-Han Kao, Zichen Wang, Ke Hao, Emilio Schadt, Michael A. Kiebish, Elder Granger, Niven R. Narain, Rong Chen, Eric E. Schadt, Li Li

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Concerns about the interpretation of subgroup analysis
Arthur M. Albuquerque, … , Carolina B. Santolia, Ashish Verma
Arthur M. Albuquerque, … , Carolina B. Santolia, Ashish Verma
Letter to the Editor COVID-19

Concerns about the interpretation of subgroup analysis

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Abstract

Authors

Arthur M. Albuquerque, Carolina B. Santolia, Ashish Verma

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The authors reply:

We appreciate Albuquerque et al.’s interest in our paper (1, 2), about which the authors of the Letter raised the concern that we did not accurately interpret the interaction test. Their Letter noted that “one should directly compare the estimates (interaction test)” and “the authors concluded that the association was only present in the African American population, which is not compatible with their analysis.”

We would like to clarify that our primary clinical question was whether use of ACE inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) is associated with the COVID-19 outcomes in each subgroup. We used a stratified analysis to answer the question, because when race/ethnicity serves as a nonspecific proxy for numerous (confounding) factors, these can be (partially) controlled for through stratification (3). Joint modeling of multiple groups is often used to gain power, but one needs to assume certain coherent distributions across different groups, which is not always true. Additionally, testing the interaction term is to assess association heterogeneity between groups; it does not directly address whether the treatment is effective in each group.

Specifically, we would like to elaborate on two points. First, our conclusion that the use of ARB was associated with a significant reduction in in-hospital mortality among African American patients but not non–African American patients was based on results from the stratified analysis. We reported that ARB in-hospital use was associated with reduced mortality in the African American stratum (OR = 0.196; 95% CI 0.074–0.516; P = 0.001) with statistical significance. On the other hand, the association in the non–African American stratum is not statistically significant (OR = 0.687; 95% CI 0.427–1.106; P = 0.122). As stated previously, our primary objective was to assess whether ACE-I/ARB use among African American patients is associated with COVID-19 mortality, rather than whether there is a difference between African American and non–African American patients. We were also aware that the estimated ORs across different stratum were not comparable as noted in (4–6).

Second, we performed the joint modeling of African American and non–African American patients as suggested by Knol and VanderWeele (6). In our study, ARB in-hospital use was associated with reduced mortality in the entire study population (OR = 0.560; 95% CI 0.371–0.846; P = 0.006). The interaction term added to the model was not significant (95% CI 0.185–1.292; P = 0.149). Interpreting interaction terms in logistic regression is complex and a significant interaction term in log-odds may not be significant in difference-in-differences for probability (7). Furthermore, the assumption of the additive effects and imbalanced sample sizes could impact the inference.

We believe these results and the interpretation are appropriate. We acknowledge that there are cases where comparing the interaction term in greater detail would be an important next step for understanding the association between COVID-19 mortality and race and ethnicity.

Footnotes

Conflict of interest: The authors have declared that no conflict of interest exists.

Reference information: J Clin Invest. 2021;132(2):e156711. https://doi.org/10.1172/JCI156711.

See the related article at In-hospital use of ACE inhibitors/angiotensin receptor blockers associates with COVID-19 outcomes in African American patients.

See the related Letter to the Editor at Concerns about the interpretation of subgroup analysis..

References
  1. Li S, et al. In-hospital use of ACE inhibitors/angiotensin receptor blockers associates with COVID-19 outcomes in African American patients. J Clin Invest. 2021;131(19):e151418.
    View this article via: JCI CrossRef PubMed Google Scholar
  2. Albuquerque AM, et al. Concerns about the interpretation of subgroup analysis. J Clin Invest. 2021;132(2):155991.
    View this article via: JCI CrossRef Google Scholar
  3. Kaufman JS. Commentary: considerations for use of racial/ethnic classification in etiologic research. Am J Epidemiol. 2001;154(4):291–298.
    View this article via: CrossRef PubMed Google Scholar
  4. Brankovic M, et al. Understanding of interaction (subgroup) analysis in clinical trials. Eur J Clin Invest. 2019;49(8):13145.
    View this article via: PubMed Google Scholar
  5. Wang R, Ware JH. Detecting moderator effects using subgroup analyses. Prev Sci. 2011;14(2):111–120.
    View this article via: PubMed Google Scholar
  6. Knol MJ, VanderWeele TJ. Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol. 2012;41(2):514–520.
    View this article via: CrossRef PubMed Google Scholar
  7. Ai C, Norton EC. Interaction terms in logit and probit models. Econ Lett. 2003;80(1):123–129.
    View this article via: CrossRef Google Scholar
Version history
  • Version 1 (December 2, 2021): In-Press Preview
  • Version 2 (January 18, 2022): Electronic publication

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