{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T18:26:43Z","timestamp":1772994403977,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T00:00:00Z","timestamp":1727654400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Genetic Epidemiology"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Increasing evidence suggests that human microbiota plays a crucial role in many diseases. Alpha diversity, a commonly used summary statistic that captures the richness and\/or evenness of the microbial community, has been associated with many clinical conditions. However, individual studies that assess the association between alpha diversity and clinical conditions often provide inconsistent results due to insufficient sample size, heterogeneous study populations and technical variability. In practice, meta\u2010analysis tools have been applied to integrate data from multiple studies. However, these methods do not consider the heterogeneity caused by sequencing protocols, and the contribution of each study to the final model depends mainly on its sample size (or variance estimate). To combine studies with distinct sequencing protocols, a robust statistical framework for integrative analysis of microbiome datasets is needed. Here, we propose a mixed\u2010effect kernel machine regression model to assess the association of alpha diversity with a phenotype of interest. Our approach readily incorporates the study\u2010specific characteristics (including sequencing protocols) to allow for flexible modeling of microbiome effect via a kernel similarity matrix. Within the proposed framework, we provide three hypothesis testing approaches to answer different questions that are of interest to researchers. We evaluate the model performance through extensive simulations based on two distinct data generation mechanisms. We also apply our framework to data from HIV reanalysis consortium to investigate gut dysbiosis in HIV infection.<\/jats:p>","DOI":"10.1002\/gepi.22596","type":"journal-article","created":{"date-parts":[[2024,10,1]],"date-time":"2024-10-01T00:28:48Z","timestamp":1727742528000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Mixed\u2010Effect Kernel Machine Regression Model for Integrative Analysis of Alpha Diversity in Microbiome Studies"],"prefix":"10.1002","volume":"49","author":[{"given":"Runzhe","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biostatistics Johns Hopkins University Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mo","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Mathematics University of Louisiana at Lafayette Lafayette Louisiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7762-3949","authenticated-orcid":false,"given":"Ni","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biostatistics Johns Hopkins University Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/10618600.2012.681213"},{"key":"e_1_2_11_3_1","first-page":"265","article-title":"Nonparametric Estimation of the Number of Classes in a Population","volume":"11","author":"Chao A.","year":"1984","journal-title":"Scandinavian Journal of Statistics"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0015216"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.2307\/2346911"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0197-2456(86)90046-2"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiu409"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmjgast-2016-000080"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","unstructured":"Efron B. andR.Thisted.1976.\u201cEstimating the Number of Unseen Species: How Many Words Did Shakespeare Know? \u201dBiometrika63 435\u2013447.https:\/\/doi.org\/10.2307\/2335721.","DOI":"10.1093\/biomet\/63.3.435"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6941.2006.00105.x"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.04.014"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21993"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.2307\/1934352"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/sim.8940"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1541-0420.2011.01675.x"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33071-9"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep30673"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2852"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2013.08.006"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1214\/009053606000001280"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.46923"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1098\/rsta.1909.0016"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000000869"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0043093"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11450"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1538-7305.1948.tb01338.x"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/163688a0"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2018.03.019"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.21717"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz258"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00130"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/biom.12332"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.05.029"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.04.003"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-73351-3_9"}],"container-title":["Genetic Epidemiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gepi.22596","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/gepi.22596","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/gepi.22596","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T15:12:49Z","timestamp":1772982769000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/gepi.22596"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,30]]},"references-count":34,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,2]]}},"alternative-id":["10.1002\/gepi.22596"],"URL":"https:\/\/doi.org\/10.1002\/gepi.22596","archive":["Portico"],"relation":{},"ISSN":["0741-0395","1098-2272"],"issn-type":[{"value":"0741-0395","type":"print"},{"value":"1098-2272","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,30]]},"assertion":[{"value":"2023-11-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-09-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e22596"}}