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BACKGROUND: Characterization of prediagnostic Parkinson's Disease (PD) and early prediction of subsequent development are critical for preventive interventions, risk stratification and understanding of disease pathology. This study aims to characterize the role of the prediagnostic period in PD and, using selected features from this period as novel interception points, construct a prediction model to accelerate the diagnosis in a real-world setting. METHODS: We constructed two sets of machine learning models: a retrospective approach highlighting exposures up to 5 years prior to PD diagnosis, and an alternative model that prospectively predicted future PD diagnosis from all individuals at their first diagnosis of a gait or tremor disorder, these being features that appeared to represent the initiation of a differential diagnostic window. RESULTS: We found many novel features captured by the retrospective models; however, the high accuracy was primarily driven from surrogate diagnoses for PD, such as gait and tremor disorders, suggesting the presence of a distinctive differential diagnostic period when the clinician already suspected PD. The model utilizing a gait/tremor diagnosis as the interception point, achieved a validation AUC of 0.874 with potential time compression to a future PD diagnosis of more than 300 days. Comparisons of predictive diagnoses between the prospective and prediagnostic cohorts suggest the presence of distinctive trajectories of PD progression based on comorbidity profiles. CONCLUSIONS: Overall, our machine learning approach allows for both guiding clinical decisions such as the initiation of neuroprotective interventions and importantly, the possibility of earlier diagnosis for clinical trials for disease modifying therapies.
Assuntos
Doença de Parkinson/diagnóstico , Marcha/fisiologia , Análise da Marcha , Humanos , Aprendizado de Máquina , Estudos Retrospectivos , Medição de Risco , TremorRESUMO
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.
RESUMO
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.
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Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.
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Células Endoteliais , Transcriptoma , Animais , Camundongos , Transcriptoma/genética , Envelhecimento/genética , Parabiose , EncéfaloRESUMO
Modeling the relationship between chemical structure and molecular activity is a key goal in drug development. Many benchmark tasks have been proposed for molecular property prediction, but these tasks are generally aimed at specific, isolated biomedical properties. In this work, we propose a new cross-modal small molecule retrieval task, designed to force a model to learn to associate the structure of a small molecule with the transcriptional change it induces. We develop this task formally as multi-view alignment problem, and present a coordinated deep learning approach that jointly optimizes representations of both chemical structure and perturbational gene expression profiles. We benchmark our results against oracle models and principled baselines, and find that cell line variability markedly influences performance in this domain. Our work establishes the feasibility of this new task, elucidates the limitations of current data and systems, and may serve to catalyze future research in small molecule representation learning.
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Benchmarking , Biologia Computacional , Estrutura MolecularRESUMO
One of the primary tools that researchers use to predict risk is the case-control study. We identify a flaw, temporal bias, that is specific to and uniquely associated with these studies that occurs when the study period is not representative of the data that clinicians have during the diagnostic process. Temporal bias acts to undermine the validity of predictions by over-emphasizing features close to the outcome of interest. We examine the impact of temporal bias across the medical literature, and highlight examples of exaggerated effect sizes, false-negative predictions, and replication failure. Given the ubiquity and practical advantages of case-control studies, we discuss strategies for estimating the influence of and preventing temporal bias where it exists.
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Pesquisa Biomédica/normas , Ensaios Clínicos como Assunto/normas , Seleção de Pacientes , Projetos de Pesquisa/normas , Viés , Pesquisa Biomédica/métodos , Pesquisa Biomédica/tendências , Estudos de Casos e Controles , Ensaios Clínicos como Assunto/métodos , Previsões , Humanos , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: We investigated the presence of non-neuromuscular phenotypes in patients affected by Spinal Muscular Atrophy (SMA), a disorder caused by a mutation in the Survival of Motor Neuron (SMN) gene, and whether these phenotypes may be clinically detectable prior to clinical signs of neuromuscular degeneration and therefore independent of muscle weakness. METHODS: We utilized a de-identified database of insurance claims to explore the health of 1,038 SMA patients compared to controls. Two analyses were performed: (1) claims from the entire insurance coverage window; and (2) for SMA patients, claims prior to diagnosis of any neuromuscular disease or evidence of major neuromuscular degeneration to increase the chance that phenotypes could be attributed directly to reduced SMN levels. Logistic regression was used to determine whether phenotypes were diagnosed at significantly different rates between SMA patients and controls and to obtain covariate-adjusted odds ratios. RESULTS: Results from the entire coverage window revealed a broad spectrum of phenotypes that are differentially diagnosed in SMA subjects compared to controls. Moreover, data from SMA patients prior to their first clinical signs of neuromuscular degeneration revealed numerous non-neuromuscular phenotypes including defects within the cardiovascular, gastrointestinal, metabolic, reproductive, and skeletal systems. Furthermore, our data provide evidence of a potential ordering of disease progression beginning with these non-neuromuscular phenotypes. CONCLUSIONS: Our data point to a direct relationship between early, detectable non-neuromuscular symptoms and SMN deficiency. Our findings are particularly important for evaluating the efficacy of SMN-increasing therapies for SMA, comparing the effectiveness of local versus systemically delivered therapeutics, and determining the optimal therapeutic treatment window prior to irreversible neuromuscular damage.
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Bases de Dados Factuais , Seguro Saúde/estatística & dados numéricos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/epidemiologia , Doenças Neuromusculares/diagnóstico , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Atrofia Muscular Espinal/fisiopatologia , Mutação , Doenças Neuromusculares/epidemiologia , Doenças Neuromusculares/fisiopatologia , Razão de Chances , Fenótipo , Análise de Regressão , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Fatores de Tempo , Adulto JovemRESUMO
The mammalian brain is complex, with multiple cell types performing a variety of diverse functions, but exactly how each cell type is affected in aging remains largely unknown. Here we performed a single-cell transcriptomic analysis of young and old mouse brains. We provide comprehensive datasets of aging-related genes, pathways and ligand-receptor interactions in nearly all brain cell types. Our analysis identified gene signatures that vary in a coordinated manner across cell types and gene sets that are regulated in a cell-type specific manner, even at times in opposite directions. These data reveal that aging, rather than inducing a universal program, drives a distinct transcriptional course in each cell population, and they highlight key molecular processes, including ribosome biogenesis, underlying brain aging. Overall, these large-scale datasets (accessible online at https://portals.broadinstitute.org/single_cell/study/aging-mouse-brain ) provide a resource for the neuroscience community that will facilitate additional discoveries directed towards understanding and modifying the aging process.
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Envelhecimento/genética , Encéfalo/crescimento & desenvolvimento , Neurônios/fisiologia , Análise de Célula Única , Transcriptoma/genética , Animais , Encéfalo/citologia , Comunicação Celular/genética , Linhagem da Célula/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ribossomos/genéticaRESUMO
The etiological underpinnings of many CNS disorders are not well understood. This is likely due to the fact that individual diseases aggregate numerous pathological subtypes, each associated with a complex landscape of genetic risk factors. To overcome these challenges, researchers are integrating novel data types from numerous patients, including imaging studies capturing broadly applicable features from patient-derived materials. These datasets, when combined with machine learning, potentially hold the power to elucidate the subtle patterns that stratify patients by shared pathology. In this study, we interrogated whether high-content imaging of primary skin fibroblasts, using the Cell Painting method, could reveal disease-relevant information among patients. First, we showed that technical features such as batch/plate type, plate, and location within a plate lead to detectable nuisance signals, as revealed by a pre-trained deep neural network and analysis with deep image embeddings. Using a plate design and image acquisition strategy that accounts for these variables, we performed a pilot study with 12 healthy controls and 12 subjects affected by the severe genetic neurological disorder spinal muscular atrophy (SMA), and evaluated whether a convolutional neural network (CNN) generated using a subset of the cells could distinguish disease states on cells from the remaining unseen control-SMA pair. Our results indicate that these two populations could effectively be differentiated from one another and that model selectivity is insensitive to batch/plate type. One caveat is that the samples were also largely separated by source. These findings lay a foundation for how to conduct future studies exploring diseases with more complex genetic contributions and unknown subtypes.
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Ensaios de Triagem em Larga Escala , Aprendizado de Máquina , Imagem Molecular , Redes Neurais de Computação , Aprendizado Profundo , Humanos , Processamento de Imagem Assistida por ComputadorRESUMO
Irradiation perturbs the homeostatic network linking parenchymal, mesenchymal, and vascular cells within tissues. Normal communication between cells through soluble, matrix, and cell-associated ligands and receptors is altered so as to set in motion a seemingly inexorable series of events aimed at tissue regeneration and healing. In late responding normal tissues where cell death is not compensated for by rapid regeneration, this process unfortunately often culminates in symptomatic complications of radiation exposure. Cytokines and their receptors are prominent in driving the cascade of molecular responses using the balance between seemingly mutually antagonistic molecules to control and direct the healing processes. There is strong evidence from preclinical models for the importance of cytokine-driven pathways in late radiation damage and growing evidence in humans for their relevance to radiation-induced disease. This review aims to show some general aspects of the molecular torrents that drive responses in irradiated tissues before and during the development of late effects. It attempts to collate some of the findings from preclinical models of late lung, central nervous system, skin, and intestinal damage and from clinical studies in the belief that understanding how irradiation perturbs the cellular communication networks will allow rationale intervention for mitigating late radiation tissue damage and carcinogenesis.