Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies
Authors: Li Ying , Saul Alice , Taylor Bruce , Ponsonby Anne-Louise , Simpson-Yap Steve , Blizzard Leigh , Broadley Simon , Lechner-Scott Jeannette ,   Ausimmune/AusLong Investigators Group, Lucas Robyn , Dear Keith , Ponsonby Anne-Louise , Dwyer Terry , van der Mei Ingrid , Blizzard Leigh , Simpson-Yap Steve , Taylor Bruce , Broadley Simon , Kilpatrick Trevor , Williams David , Lechner-Scott Jeanette , Shaw Cameron , Chapman Caron , Coulthard Alan , Pender Michael , Valery Patricia , Karabudak Rana , Patti Francesco , Eichau Sara , Onofrj Marco , Ozakbas Serkan , Horakova Dana , Kubala Havrdova Eva , Grand’Maison Francois , Alroughani Raed , Gerlach Oliver , Amato Maria Pia , Altintas Ayse , Girard Marc , Duquette Pierre , Blanco Yolanda , Ramo-Tello Cristina , Laureys Guy , Kalincik Tomas , Khoury Samia J. , Shaygannejad Vahid , Etemadifar Masoud , Singhal Bhim , Mrabet Saloua , Foschi Matteo , Habek Mario , John Nevin , Hughes Stella , McCombe Pamela , Ampapa Radek , van der Walt Anneke , Butzkueven Helmut , de Gans Koen , McGuigan Chris , Oreja-Guevara Celia , Sa Maria Jose , Petersen Thor , Al-Harbi Talal , Sempere Angel Perez , Van Wijmeersch Bart , Grigoriadis Nikolaos , Prevost Julie , Gray Orla , Castillo-Triviño Tamara , Macdonell Richard , Lugaresi Alessandra , Sajedi Seyed Aidin ,   MSBase, Karabudak Rana , Patti Francesco , Eichau Sara , Onofrj Marco , Ozakbas Serkan , Horakova Dana , Kubala Havrdova Eva , Grand’Maison Francois , Alroughani Raed , Gerlach Oliver , Amato Maria Pia , Altintas Ayse , Girard Marc , Duquette Pierre , Blanco Yolanda , Ramo-Tello Cristina , Laureys Guy , Kalincik Tomas , Khoury Samia J. , Shaygannejad Vahid , Etemadifar Masoud , Singhal Bhim , Mrabet Saloua , Foschi Matteo , Habek Mario , John Nevin , Hughes Stella , McCombe Pamela , Ampapa Radek , van der Walt Anneke , Butzkueven Helmut , de Gans Koen , McGuigan Chris , Oreja-Guevara Celia , Sa Maria Jose , Petersen Thor , Al-Harbi Talal , Sempere Angel Perez , Van Wijmeersch Bart , Grigoriadis Nikolaos , Prevost Julie , Gray Orla , Castillo-Triviño Tamara , Macdonell Richard , Lugaresi Alessandra , Sajedi Seyed Aidin , Campbell Jamie , Zwanikken Cees , van Pesch Vincent , Izquierdo Guillermo , Maimone Davide , Weinstock-Guttman Bianca , Terzi Murat , Prat Alexandre , Boz Cavit , Zakaria Magd , van Hijfte Liesbeth , Yamout Bassem , Grammond Pierre , Rojas Juan Ignacio , Spitaleri Daniele , Lechner-Scott Jeannette , Buzzard Katherine , Skibina Olga , Shalaby Nevin , Gouider Riadh , Cristiano Edgardo , Kuhle Jens , Slee Mark , Turkoglu Recai , Sinnige L. G. F. , Sanchez-Menoyo Jose Luis , Solaro Claudio , Cartechini Elisabetta , Iuliano Gerardo , Taylor Bruce , Talaat Farouk , Barnett Michael , Oh Jiwon , Rio Maria Edite , Fernandez-Bolaños Ricardo , Khurana Dheeraj , Besora Sarah , Soysal Aysun , Saladino Maria Laura , Den Braber-Moerland Leontien , Cabrera-Gomez Jose Antonio , Willekens Barbara , Garber Justin , Brola Waldemar , Fragoso Yara , Al-Asmi Abdullah , Kermode Allan , Fabis-Pedrini Marzena , Lapointe Emmanuelle , Hodgkinson Suzanne , Vasconcelos Claudia , Lalive Patrice , Shaw Cameron , Gobbi Claudio , Shalaby Nevin , Cardenas-Robledo Simon , Hardy Todd , Bacile Elizabeth Alejandra , Pucci Eugenio , Parratt John , Baghbanian Seyed Mohammad , Vrech Carlos , Field Deborah , Kister Ilya , Schepel Jan , Joseph Joyce Pauline , Cambron Melissa , Deri Norma , Sirbu Carmen-Adella , Moore Fraser , Tsolaki Magda , Boggild Mike , Tsai Nai-Wen , Shuey Neil , Flechter Shlomo , Mihaela Simu , Jimenez Alejandro Jose Diaz , Quek Chu Zhen , Decoo Danny , Karussis Dimitrios , Aguera-Morales Eduardo , Roullet Etienne , Tan Ik Lin , Alkhaboori Jabir , Inshasi Jihad , Kotkata Karim , Gross-Paju Katrin , Simo Magdolna , Al Khawajah Mona , Razazian Nazanin , Charest Stephane , Csepany Tunde , Santiago Vetere , Liu Yaou , van der Mei Ingrid 
Published: September 2023

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case–control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.