Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

Martínková, J; Quevenco, Frances‐Catherine; Karcher, Hélène; Ferrari, Alberto; Sandset, Else Charlotte; Szoeke, Cassandra; Hort, Jakub; Schmidt, Reinhold; Chadha, Antonella Santuccione; Ferretti, Maria Teresa

doi:10.1001/jamanetworkopen.2021.24124

Cited by 38 publications

(31 citation statements)

References 110 publications

(471 reference statements)

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“…Indeed, the number of publications on sex differences in diseases has substantially increased in the last decade (trends data from PubMed). Similar increasing temporal trends were observed in two recent analyses of reporting of results by sex in clinical trials of acute stroke therapies and Alzheimer's disease 13,22 . However, the reporting of outcomes by sex is still largely suboptimal as only 40% of RCTs of AF published in 2020 and 2021 reported sex‐specific outcomes.…”

Section: Discussionsupporting

confidence: 68%

“…Similar increasing temporal trends were observed in two recent analyses of reporting of results by sex in clinical trials of acute stroke therapies and Alzheimer's disease. 13,22 However, the reporting of outcomes by sex is still largely suboptimal as only 40% of RCTs of AF published in 2020 and 2021 reported sex-specific outcomes. We observe higher rates of reporting in NEJM (87.5%) and Lancet (50.0%), in keeping with a 2016 review on sex-related reporting in RCTs in the NEJM and Lancet journals in which 48% of trials reported results by sex, 15 and with a more recent review on trials of acute stroke therapies which showed 61% and 40% sex-specific reporting in trials published in the NEJM and Lancet, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Sex disparities in enrollment and reporting of outcomes by sex in contemporary clinical trials of atrial fibrillation

Noubiap

Thomas

Nyaga

et al. 2022

Cardiovasc electrophysiol

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Background: Underrepresentation of females in randomized controlled trials (RCTs) limits generalizability and quality of the evidence guiding treatment of females. This study aimed to measure the sex disparities in participants' recruitment in RCTs of atrial fibrillation (AF) and determine associated factors, and to describe the frequency of outcomes reported by sex.Methods: MEDLINE was searched to identify RCTs of AF published between January 1, 2011, and November 20, 2021, in 12 top-tier journals. We measured the enrollment of females using the enrollment disparity difference (EDD) which is the difference between the proportion of females in the trial and the proportion of females with AF in the underlying general population (obtained from the Global Burden of Disease). Random-effects meta-analyses of the EDD were performed, and multivariable meta-regression was used to explore factors associated with disparity estimates. We also determined the proportion of trials that included sex-stratified results.Results: Out of 1133 records screened, 142 trials were included, reporting on a total of 133 532 participants. The random-effects summary EDD was −0.125 (95% confidence interval [CI] = −0.143 to −0.108), indicating that females were underenrolled by 12.5 percentage points. Female enrollment was higher in trials with higher sample size (<250 vs. >750, adjusted odds ratio [aOR] 1.065, 95% CI:1.008-1.125), higher mean participants' age (aOR: 1.006, 95% CI: 1.002-1.009), and lower in trials conducted in North America compared to Europe (aOR: 0.945, 95% CI: 0.898-0.995). Only 36 trials (25.4%) reported outcomes by sex, and of these 29 (80.6%) performed statistical testing of the sex-by-treatment interaction. Conclusion:Females remain substantially less represented in RCTs of AF, and sexstratified reporting of primary outcomes is infrequent. These findings call for urgent

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Sex disparities in enrollment and reporting of outcomes by sex in contemporary clinical trials of atrial fibrillation

Noubiap

Thomas

Nyaga

et al. 2022

Cardiovasc electrophysiol

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“…Sex-related differences in absorption and excretion, distribution and metabolism of drugs have been described and more adverse drug reactions have been reported in females compared with males ( Whitley and Lindsey, 2009 ) highlighting sexual dimorphic responses to drugs, notably drugs that affect the CNS. In the context of AD, a recent review and metanalysis reported that only 7 out of the 56 randomized clinical trials in AD included reported sex-stratified results and concluded ( Martinkova et al, 2021 ) and the relative lack of data on sex-related differences in drug efficacy has been noted ( Ferretti et al, 2018 ). In the light of this, a call has been made for specific analysis of gender effects on drug treatments in AD ( Schwartz and Weintraub, 2021 ) but this cannot be confined to AD and the principle should apply broadly, but particularly in conditions where clear sex-related differences in disease incidence exists.…”

Section: Discussionmentioning

confidence: 99%

Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

Lynch

2022

Front. Aging Neurosci.

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One area of microglial biology that has been relatively neglected until recently is sex differences and this is in spite of the fact that sex is a risk factor in several diseases that are characterized by neuroinflammation and, by extension, microglial activation. Why these sex differences exist is not known but the panoply of differences extend to microglial number, genotype and phenotype. Significantly, several of these sex-related differences are also evident in health and change during life emphasizing the dynamic and plastic nature of microglia. This review will consider how age impacts on sex-related differences in microglia and ask whether the advancement of personalized medicine demands that a greater focus is placed on studying sex-related differences in microglia in Alzheimer’s disease, Parkinson’s disease and models of inflammatory stress and trauma in order to make true progress in dealing with these conditions.

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“…Currently, clinical trials of drugs for treatment of AD have a very high degree of failure, suggesting that individual factors should be taken into account both in searching new treatments and in designing clinical trials [42]. Biological sex is one such factor; a recent meta-analysis showed that the proportion of women enrolled in clinical trials for AD is lower than in the general AD population, and that it correlates with severity of symptoms in the enrolled population [43]. An appraisal of the impact of sex on cognitive decline and treatment response in Alzheimer is pivotal to build personalized treatment tailored to the unmet clinical needs of the patients.…”

Section: Discussionmentioning

confidence: 99%

“…Recent research supports the need to account for sex in investigating prospective treatments for AD [43] This should be integrated with the most powerful recent developments in digital medicine to build models of disease development that can fully integrate the effect of sex, digital biomarker technology being one of the most promising tools. The final objective is to build an integrated framework for sex-stratified prediction, monitoring and personalized treatment of neurodegenerative diseases, as supported for example by the Alzheimer's Precision Medicine Initiative [55].…”

Section: Discussionmentioning

confidence: 99%

Digital biomarkers and sex impacts in Alzheimer’s disease management — potential utility for innovative 3P medicine approach

Harms¹,

Ferrari

Meier³

et al. 2022

EPMA Journal

Self Cite

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Digital biomarkers are defined as objective, quantifiable physiological and behavioral data that are collected and measured by means of digital devices. Their use has revolutionized clinical research by enabling high-frequency, longitudinal, and sensitive measurements. In the field of neurodegenerative diseases, an example of a digital biomarker-based technology is instrumental activities of daily living (iADL) digital medical application, a predictive biomarker of conversion from mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) to dementia due to AD in individuals aged 55 + . Digital biomarkers show promise to transform clinical practice. Nevertheless, their use may be affected by variables such as demographics, genetics, and phenotype. Among these factors, sex is particularly important in Alzheimer’s, where men and women present with different symptoms and progression patterns that impact diagnosis. In this study, we explore sex differences in Altoida’s digital medical application in a sample of 568 subjects consisting of a clinical dataset (MCI and dementia due to AD) and a healthy population. We found that a biological sex-classifier, built on digital biomarker features captured using Altoida’s application, achieved a 75% ROC-AUC (receiver operating characteristic — area under curve) performance in predicting biological sex in healthy individuals, indicating significant differences in neurocognitive performance signatures between males and females. The performance dropped when we applied this classifier to more advanced stages on the AD continuum, including MCI and dementia, suggesting that sex differences might be disease-stage dependent. Our results indicate that neurocognitive performance signatures built on data from digital biomarker features are different between men and women. These results stress the need to integrate traditional approaches to dementia research with digital biomarker technologies and personalized medicine perspectives to achieve more precise predictive diagnostics, targeted prevention, and customized treatment of cognitive decline.

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Proportion of Women and Reporting of Outcomes by Sex in Clinical Trials for Alzheimer Disease

Cited by 38 publications

References 110 publications

Sex disparities in enrollment and reporting of outcomes by sex in contemporary clinical trials of atrial fibrillation

Sex disparities in enrollment and reporting of outcomes by sex in contemporary clinical trials of atrial fibrillation

Exploring Sex-Related Differences in Microglia May Be a Game-Changer in Precision Medicine

Digital biomarkers and sex impacts in Alzheimer’s disease management — potential utility for innovative 3P medicine approach

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