Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort

Helena Oakey; Lynne C Giles; Rebecca L Thomson; Kim-Anh Lê Cao; Pat Ashwood; James D Brown; Emma J Knight; Simon C Barry; Maria E Craig; Peter G Colman; Elizabeth A Davis; Emma E Hamilton-Williams; Leonard C Harrison; Aveni Haynes; Ki Wook Kim; Kylie-Ann Mallitt; Kelly McGorm; Grant Morahan; William D Rawlinson; Richard O Sinnott; Georgia Soldatos; John M Wentworth; Jennifer J Couper; Megan A S Penno; ENDIA Study Group

doi:10.1080/07853890.2023.2198255

Protocol for a nested case-control study design for omics investigations in the Environmental Determinants of Islet Autoimmunity cohort

Ann Med. 2023 Dec;55(1):2198255. doi: 10.1080/07853890.2023.2198255.

Authors

Helena Oakey¹, Lynne C Giles², Rebecca L Thomson¹, Kim-Anh Lê Cao³, Pat Ashwood¹, James D Brown¹, Emma J Knight¹, Simon C Barry¹, Maria E Craig^{4

5}, Peter G Colman^{6

7}, Elizabeth A Davis⁸, Emma E Hamilton-Williams⁹, Leonard C Harrison^{10

11}, Aveni Haynes¹², Ki Wook Kim⁴, Kylie-Ann Mallitt^{13

14}, Kelly McGorm¹, Grant Morahan¹⁵, William D Rawlinson¹⁶, Richard O Sinnott¹⁷, Georgia Soldatos¹⁸, John M Wentworth^{6

10}, Jennifer J Couper^{1

19}, Megan A S Penno¹; ENDIA Study Group

Affiliations

¹ Adelaide Medical School, Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.
² School of Public Health, The University of Adelaide, Adelaide, South Australia, Australia.
³ Melbourne Integrative Genomics, School of Mathematics and Statistics, University of Melbourne, Melbourne, Victoria, Australia.
⁴ School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
⁵ Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁶ Department of Diabetes and Endocrinology, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁷ Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Telethon Kids Institute Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
⁹ Faculty of Medicine, Frazer Institute, The University of Queensland Translational Research Institute, Brisbane, Queensland, Australia.
¹⁰ Population Health and Immunity Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
¹¹ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
¹² Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
¹³ Faculty of Medicine and Health, Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.
¹⁴ School of Clinical Medicine - Psychiatry and Mental Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁵ Centre for Diabetes Research, Harry Perkins Institute of Medical Research, The University of Western Australia, Perth, Western Australia, Australia.
¹⁶ Virology Research Laboratory, Serology and Virology Division, South Eastern Area Laboratory Services Microbiology, Prince of Wales Hospital, Sydney, New South Wales, Australia.
¹⁷ Melbourne eResearch Group, School of Computing and Information Services, University of Melbourne, Melbourne, Victoria, Australia.
¹⁸ Diabetes and Vascular Medicine Unit, Monash Health, Melbourne, Victoria, Australia.
¹⁹ Endocrinology and Diabetes Centre, Women's and Children's Hospital, Adelaide, South Australia, Australia.

Abstract

Background: The Environmental Determinants of Islet Autoimmunity (ENDIA) pregnancy-birth cohort investigates the developmental origins of type 1 diabetes (T1D), with recruitment between 2013 and 2019. ENDIA is the first study in the world with comprehensive data and biospecimen collection during pregnancy, at birth and through childhood from at-risk children who have a first-degree relative with T1D. Environmental exposures are thought to drive the progression to clinical T1D, with pancreatic islet autoimmunity (IA) developing in genetically susceptible individuals. The exposures and key molecular mechanisms driving this progression are unknown. Persistent IA is the primary outcome of ENDIA; defined as a positive antibody for at least one of IAA, GAD, ZnT8 or IA2 on two consecutive occasions and signifies high risk of clinical T1D.Method: A nested case-control (NCC) study design with 54 cases and 161 matched controls aims to investigate associations between persistent IA and longitudinal omics exposures in ENDIA. The NCC study will analyse samples obtained from ENDIA children who have either developed persistent IA or progressed to clinical T1D (cases) and matched control children at risk of developing persistent IA. Control children were matched on sex and age, with all four autoantibodies absent within a defined window of the case's onset date. Cases seroconverted at a median of 1.37 years (IQR 0.95, 2.56). Longitudinal omics data generated from approximately 16,000 samples of different biospecimen types, will enable evaluation of changes from pregnancy through childhood.Conclusions: This paper describes the ENDIA NCC study, omics platform design considerations and planned univariate and multivariate analyses for its longitudinal data. Methodologies for multivariate omics analysis with longitudinal data are discovery-focused and data driven. There is currently no single multivariate method tailored specifically for the longitudinal omics data that the ENDIA NCC study will generate and therefore omics analysis results will require either cross validation or independent validation.KEY MESSAGESThe ENDIA nested case-control study will utilize longitudinal omics data on approximately 16,000 samples from 190 unique children at risk of type 1 diabetes (T1D), including 54 who have developed islet autoimmunity (IA), followed during pregnancy, at birth and during early childhood, enabling the developmental origins of T1D to be explored.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoantibodies
Autoimmunity / genetics
Case-Control Studies
Child
Child, Preschool
Diabetes Mellitus, Type 1* / etiology
Diabetes Mellitus, Type 1* / genetics
Female
Genetic Predisposition to Disease
Humans
Infant
Infant, Newborn
Islets of Langerhans*
Pregnancy

Substances

Autoantibodies

Associated data

ANZCTR/ACTRN12613000794707

Grants and funding

This research was supported by JDRF Australia, the recipient of the Commonwealth of Australia grant for Accelerated Research under the Medical Research Future Fund and with funding from The Leona M. and Harry B. Helmsley Charitable Trust (grant keys 3-SRA-2020-966-M-N, 3-SRA-2019-899-M-N, 2-SRA-2021-1083-M-B, 2-SRA-2022-1094-M-B, 2-SRA-2021-1085-M-B). In addition, support was provided by The National Health and Medical Research Council of Australia (APP1078106), JDRF Australia Pilot and Innovation Award scheme (JDRF 2-SRA-2022-1100-M-B), JDRF International Strategic Research Award scheme (JDRF 3-SRA-2017-417-A-N, 3-SRA-2019-730-S-B, 17-2013-526), The Leona M. and Harry B. Helmsley Charitable Trust (G-2112-04908, G-2103-05117) and Diabetes SA. KWK and AH are the recipients of JDRF International Postdoctoral Fellowships (JDRF 3-PDF-2020-940-A-N and 3-PDF-2020-939-A-N). LCH is the recipient of an NHMRC Leadership Investigator Grant (APP1173945). MEC is the recipient of an NHMRC Practitioner fellowship (APP1136735).