Dataset Information

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

ABSTRACT: 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.

SUBMITTER: Li Y

PROVIDER: S-EPMC10770262 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

Li Ying Y Saul Alice A Taylor Bruce B Ponsonby Anne-Louise AL Simpson-Yap Steve S Blizzard Leigh L Broadley Simon S Lechner-Scott Jeannette J Karabudak Rana R Patti Francesco F Eichau Sara S Onofrj Marco M Ozakbas Serkan S Horakova Dana D Kubala Havrdova Eva E Grand'Maison Francois F Alroughani Raed R Gerlach Oliver O Amato Maria Pia MP Altintas Ayse A Girard Marc M Duquette Pierre P Blanco Yolanda Y Ramo-Tello Cristina C Laureys Guy G Kalincik Tomas T Khoury Samia J SJ Shaygannejad Vahid V Etemadifar Masoud M Singhal Bhim B Mrabet Saloua S Foschi Matteo M Habek Mario M John Nevin N Hughes Stella S McCombe Pamela P Ampapa Radek R van der Walt Anneke A Butzkueven Helmut H de Gans Koen K McGuigan Chris C Oreja-Guevara Celia C Sa Maria Jose MJ Petersen Thor T Al-Harbi Talal T Sempere Angel Perez AP Van Wijmeersch Bart B Grigoriadis Nikolaos N Prevost Julie J Gray Orla O Castillo-Triviño Tamara T Macdonell Richard R Lugaresi Alessandra A Sajedi Seyed Aidin SA van der Mei Ingrid I

Journal of neurology 20230928 1

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 utiliz ...[more]

PMID: 37768389

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Project description:Our inability to reliably predict disease outcomes in multiple sclerosis remains an issue for clinicians and clinical trialists. This study aims to create, from available clinical, genetic and environmental factors; a clinical-environmental-genotypic prognostic index to predict the probability of new relapses and disability worsening. The analyses cohort included prospectively assessed multiple sclerosis cases (N = 253) with 2858 repeated observations measured over 10 years. N = 219 had been diagnosed as relapsing-onset, while N = 34 remained as clinically isolated syndrome by the 10th-year review. Genotype data were available for 199 genetic variants associated with multiple sclerosis risk. Penalized Cox regression models were used to select potential genetic variants and predict risk for relapses and/or worsening of disability. Multivariable Cox regression models with backward elimination were then used to construct clinical-environmental, genetic and clinical-environmental-genotypic prognostic index, respectively. Robust time-course predictions were obtained by Landmarking. To validate our models, Weibull calibration models were used, and the Chi-square statistics, Harrell's C-index and pseudo-R 2 were used to compare models. The predictive performance at diagnosis was evaluated using the Kullback-Leibler and Brier (dynamic) prediction error (reduction) curves. The combined index (clinical-environmental-genotypic) predicted a quadratic time-dynamic disease course in terms of worsening (HR = 2.74, CI: 2.00-3.76; pseudo-R 2=0.64; C-index = 0.76), relapses (HR = 2.16, CI: 1.74-2.68; pseudo-R 2 = 0.91; C-index = 0.85), or both (HR = 3.32, CI: 1.88-5.86; pseudo-R 2 = 0.72; C-index = 0.77). The Kullback-Leibler and Brier curves suggested that for short-term prognosis (≤5 years from diagnosis), the clinical-environmental components of disease were more relevant, whereas the genetic components reduced the prediction errors only in the long-term (≥5 years from diagnosis). The combined components performed slightly better than the individual ones, although their prognostic sensitivities were largely modulated by the clinical-environmental components. We have created a clinical-environmental-genotypic prognostic index using relevant clinical, environmental, and genetic predictors, and obtained robust dynamic predictions for the probability of developing new relapses and worsening of symptoms in multiple sclerosis. Our prognostic index provides reliable information that is relevant for long-term prognostication and may be used as a selection criterion and risk stratification tool for clinical trials. Further work to investigate component interactions is required and to validate the index in independent data sets.

Project description:BackgroundPublication bias is a form of scientific misconduct. It threatens the validity of research results and the credibility of science. Although several tests on publication bias exist, no in-depth evaluations are available that examine which test performs best for different research settings.MethodsFour tests on publication bias, Egger's test (FAT), p-uniform, the test of excess significance (TES), as well as the caliper test, were evaluated in a Monte Carlo simulation. Two different types of publication bias and its degree (0%, 50%, 100%) were simulated. The type of publication bias was defined either as file-drawer, meaning the repeated analysis of new datasets, or p-hacking, meaning the inclusion of covariates in order to obtain a significant result. In addition, the underlying effect (β = 0, 0.5, 1, 1.5), effect heterogeneity, the number of observations in the simulated primary studies (N = 100, 500), and the number of observations for the publication bias tests (K = 100, 1,000) were varied.ResultsAll tests evaluated were able to identify publication bias both in the file-drawer and p-hacking condition. The false positive rates were, with the exception of the 15%- and 20%-caliper test, unbiased. The FAT had the largest statistical power in the file-drawer conditions, whereas under p-hacking the TES was, except under effect heterogeneity, slightly better. The CTs were, however, inferior to the other tests under effect homogeneity and had a decent statistical power only in conditions with 1,000 primary studies.DiscussionThe FAT is recommended as a test for publication bias in standard meta-analyses with no or only small effect heterogeneity. If two-sided publication bias is suspected as well as under p-hacking the TES is the first alternative to the FAT. The 5%-caliper test is recommended under conditions of effect heterogeneity and a large number of primary studies, which may be found if publication bias is examined in a discipline-wide setting when primary studies cover different research problems.

Dataset Information

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

Publications

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

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