Phenotypic overlap between rare disease patients and variant carriers in a large population cohort informs biological mechanisms.

The biological mechanisms giving rise to the extreme symptoms exhibited by rare disease patients are complex, heterogenous, and difficult to discern. Understanding these mechanisms is critical for developing treatments that address the underlying causes of diseases rather than merely the presenting symptoms. Moreover, the same dysfunctional biological mechanisms implicated in rare recessive diseases may also lead to milder and potentially preventable symptoms in carriers in the general population. Seizures are a common, extreme phenotype that can result from diverse and often elusive biological pathways in patients with ultrarare or undiagnosed disorders. In this pilot study, we present an approach to understand the biological pathways leading to seizures in patients from the Undiagnosed Diseases Network (UDN) by analyzing aggregated genotype and phenotype data from the UK Biobank (UKB). Specifically, we look for enriched phenotypes across UKB participants who harbor rare variants in the same gene known or suspected to be causally implicated in a UDN patient's recessively manifesting disorder. Analyzing these milder but related associated phenotypes in UKB participants can provide insight into the disease-causing molecular mechanisms at play in the rare disease UDN patient. We present six vignettes of undiagnosed patients experiencing seizures as part of their recessive genetic condition, and we discuss the potential mechanisms underlying the spectrum of symptoms associated with UKB participants to the severe presentations exhibited by UDN patients. We find that in our set of rare disease patients, seizures may result from diverse, multi-step pathways that involve multiple body systems. Analyses of large-scale population cohorts such as the UKB can be a critical tool to further our understanding of rare diseases in general.

Disease progression strikingly differs in research and real-world Parkinson's populations.

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data, and advances in natural language processing, particularly large language models, allow for a more granular comparison of populations than previously possible. This study includes two research populations and two real-world data-derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using a manually validated natural language processing with a large language model to extract measurements of PD progression. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p < 0.001; mini-mental state exam median decline 0.28 vs. 0.11, p < 0.001; and clinically recognized cognitive decline, p = 0.001). In real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p < 0.001). After diagnosis, in real-world cohorts, treatment with PD medications has initiated an average of 2.3 years later (95% CI: [2.1-2.4]; p < 0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real-world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.

Disease progression strikingly differs in research and real-world Parkinson's populations.

Characterization of Parkinson's disease (PD) progression using real-world evidence could guide clinical trial design and identify subpopulations. Efforts to curate research populations, the increasing availability of real-world data and recent advances in natural language processing, particularly large language models, allow for a more granular comparison of populations and the methods of data collection describing these populations than previously possible. This study includes two research populations and two real-world data derived (RWD) populations. The research populations are the Harvard Biomarkers Study (HBS, N = 935), a longitudinal biomarkers cohort study with in-person structured study visits; and Fox Insights (N = 36,660), an online self-survey-based research study of the Michael J. Fox Foundation. Real-world cohorts are the Optum Integrated Claims-electronic health records (N = 157,475), representing wide-scale linked medical and claims data and de-identified data from Mass General Brigham (MGB, N = 22,949), an academic hospital system. Structured, de-identified electronic health records data at MGB are supplemented using natural language processing with a large language model to extract measurements of PD progression. This extraction process is manually validated for accuracy. Motor and cognitive progression scores change more rapidly in MGB than HBS (median survival until H&Y 3: 5.6 years vs. >10, p<0.001; mini-mental state exam median decline 0.28 vs. 0.11, p<0.001; and clinically recognized cognitive decline, p=0.001). In the real-world populations, patients are diagnosed more than eleven years later (RWD mean of 72.2 vs. research mean of 60.4, p<0.001). After diagnosis, in real-world cohorts, treatment with PD medications is initiated 2.3 years later on average (95% CI: [2.1-2.4]; p<0.001). This study provides a detailed characterization of Parkinson's progression in diverse populations. It delineates systemic divergences in the patient populations enrolled in research settings vs. patients in the real world. These divergences are likely due to a combination of selection bias and real population differences, but exact attribution of the causes is challenging using existing data. This study emphasizes a need to utilize multiple data sources and to diligently consider potential biases when planning, choosing data sources, and performing downstream tasks and analyses.

Diversity in Machine Learning: A Systematic Review of Text-Based Diagnostic Applications.

OBJECTIVE: As the storage of clinical data has transitioned into electronic formats, medical informatics has become increasingly relevant in providing diagnostic aid. The purpose of this review is to evaluate machine learning models that use text data for diagnosis and to assess the diversity of the included study populations. METHODS: We conducted a systematic literature review on three public databases. Two authors reviewed every abstract for inclusion. Articles were included if they used or developed machine learning algorithms to aid in diagnosis. Articles focusing on imaging informatics were excluded. RESULTS: From 2,260 identified papers, we included 78. Of the machine learning models used, neural networks were relied upon most frequently (44.9%). Studies had a median population of 661.5 patients, and diseases and disorders of 10 different body systems were studied. Of the 35.9% (N = 28) of papers that included race data, 57.1% (N = 16) of study populations were majority White, 14.3% were majority Asian, and 7.1% were majority Black. In 75% (N = 21) of papers, White was the largest racial group represented. Of the papers included, 43.6% (N = 34) included the sex ratio of the patient population. DISCUSSION: With the power to build robust algorithms supported by massive quantities of clinical data, machine learning is shaping the future of diagnostics. Limitations of the underlying data create potential biases, especially if patient demographics are unknown or not included in the training. CONCLUSION: As the movement toward clinical reliance on machine learning accelerates, both recording demographic information and using diverse training sets should be emphasized. Extrapolating algorithms to demographics beyond the original study population leaves large gaps for potential biases.