Objectives In multisite human immunodeficiency virus (HIV) observational cohorts, clustering of observations often occurs within sites. Ignoring clustering may lead to “Simpson's paradox” (SP) where the trend observed in the aggregated data is reversed when the groups are separated. This study aimed to investigate the SP in an Asian HIV cohort and the effects of site-level adjustment through various Cox regression models. Study Design and Setting Survival time from combination antiretroviral therapy (cART) initiation was analyzed using four Cox models: (1) no site adjustment; (2) site as a fixed effect; (3) stratification through site; and (4) shared frailty on site. Results A total of 6,454 patients were included from 23 sites in Asia. SP was evident in the year of cART initiation variable. Model (1) shows the hazard ratio (HR) for years 2010–2014 was higher than the HR for 2006–2009, compared to 2003–2005 (HR = 0.68 vs. 0.61). Models (2)–(4) consistently implied greater improvement in survival for those who initiated in 2010–2014 than 2006–2009 contrasting findings from model (1). The effects of other significant covariates on survival were similar across four models. Conclusions Ignoring site can lead to SP causing reversal of treatment effects. Greater emphasis should be made to include site in survival models when possible.
Bibliographical noteFunding Information:
Author's contributions: A.J. conceptualized analysis ideas, performed data collection, data analysis, drafting of manuscript, and manuscript submission. M.L. initiated concept ideas, provided analysis inputs, reviewed, and edited the manuscript. S.K. provided analysis inputs, reviewed, and edited the manuscript. E.C., A.H., S.Ta., S.Te., and G.W. provided analysis inputs and reviewed the manuscript. P.S.L. and S.K. reviewed the final manuscript. All authors have approved of the final version of the manuscript. The TREAT Asia HIV Observational Database: PS Ly ∗ and V Khol, National Center for HIV/AIDS, Dermatology & STDs, Phnom Penh, Cambodia; FJ Zhang ∗ , HX Zhao, and N Han, Beijing Ditan Hospital, Capital Medical University, Beijing, China; MP Lee ∗ , ‡ , PCK Li, W Lam, and YT Chan, Queen Elizabeth Hospital, Hong Kong, China; N Kumarasamy ∗ , S Saghayam, and C Ezhilarasi, Chennai Antiviral Research and Treatment Clinical Research Site (CART CRS), YRGCARE Medical Center, VHS, Chennai, India; S Pujari ∗ , K Joshi, S Gaikwad, and A Chitalikar, Institute of Infectious Diseases, Pune, India; TP Merati ∗, † , DN Wirawan, and F Yuliana, Faculty of Medicine Udayana University & Sanglah Hospital, Bali, Indonesia; E Yunihastuti ∗ , D Imran, and A Widhani, Working Group on AIDS Faculty of Medicine, University of Indonesia/Cipto Mangunkusumo Hospital, Jakarta, Indonesia; S Oka ∗ , J Tanuma, and T Nishijima, National Center for Global Health and Medicine, Tokyo, Japan; JY Choi ∗ , Na S, and JM Kim, Division of Infectious Diseases, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea; BLH Sim ∗ , YM Gani, and R David, Hospital Sungai Buloh, Sungai Buloh, Malaysia; A Kamarulzaman ∗ , SF Syed Omar, S Ponnampalavanar, and I Azwa, University Malaya Medical Center, Kuala Lumpur, Malaysia; M Mustafa and N Nordin, Hospital Raja Perempuan Zainab II, Kota Bharu, Malaysia; R Ditangco ∗ , E Uy, and R Bantique, Research Institute for Tropical Medicine, Manila, Philippines; WW Wong ∗ , WW Ku, and PC Wu, Taipei Veterans General Hospital, Taipei, Taiwan; OT Ng ∗ , PL Lim, LS Lee, and R Martinez-Vega, Tan Tock Seng Hospital, Singapore; P Phanuphak ∗ , K Ruxrungtham, A Avihingsanon, and P Chusut, HIV-NAT/Thai Red Cross AIDS Research Center, Bangkok, Thailand; S Kiertiburanakul ∗ , S Sungkanuparph, L Chumla, and N Sanmeema, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; R Chaiwarith ∗ , T Sirisanthana, W Kotarathititum, and J Praparattanapan, Research Institute for Health Sciences, Chiang Mai, Thailand; P Kantipong ∗ and P Kambua, Chiangrai Prachanukroh Hospital, Chiang Rai, Thailand; W Ratanasuwan ∗ and R Sriondee, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; KV Nguyen ∗ , VH Bui, DTH Nguyen, and DT Nguyen, National Hospital for Tropical Diseases, Hanoi, Vietnam; TT Pham ∗ , DD Cuong, and HL Ha, Bach Mai Hospital, Hanoi, Vietnam; AH Sohn ∗ , N Durier ∗ , and B Petersen, TREAT Asia, amfAR—The Foundation for AIDS Research, Bangkok, Thailand; and DA Cooper, MG Law ∗ , A Jiamsakul ∗ , and DC Boettiger, The Kirby Institute, UNSW Australia, Sydney, Australia. ∗ indicates TAHOD Steering Committee member; † indicates Steering Committee Chair; and ‡ indicates co-Chair.
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