A spatially specified systems pharmacology therapy for axonal recovery after injury.

There are no known drugs or drug combinations that promote substantial central nervous system axonal regeneration after injury. We used systems pharmacology approaches to model pathways underlying axonal growth and identify a four-drug combination that regulates multiple subcellular processes in the cell body and axons using the optic nerve crush model in rats. We intravitreally injected agonists HU-210 (cannabinoid receptor-1) and IL-6 (interleukin 6 receptor) to stimulate retinal ganglion cells for axonal growth. We applied, in gel foam at the site of nerve injury, Taxol to stabilize growing microtubules, and activated protein C to clear the debris field since computational models predicted that this drug combination regulating two subcellular processes at the growth cone produces synergistic growth. Physiologically, drug treatment restored or preserved pattern electroretinograms and some of the animals had detectable visual evoked potentials in the brain and behavioral optokinetic responses. Morphology experiments show that the four-drug combination protects axons or promotes axonal regrowth to the optic chiasm and beyond. We conclude that spatially targeted drug treatment is therapeutically relevant and can restore limited functional recovery.

Clustering rare diseases within an ontology-enriched knowledge graph.

OBJECTIVE: Identifying sets of rare diseases with shared aspects of etiology and pathophysiology may enable drug repurposing. Toward that aim, we utilized an integrative knowledge graph to construct clusters of rare diseases. MATERIALS AND METHODS: Data on 3242 rare diseases were extracted from the National Center for Advancing Translational Science Genetic and Rare Diseases Information center internal data resources. The rare disease data enriched with additional biomedical data, including gene and phenotype ontologies, biological pathway data, and small molecule-target activity data, to create a knowledge graph (KG). Node embeddings were trained and clustered. We validated the disease clusters through semantic similarity and feature enrichment analysis. RESULTS: Thirty-seven disease clusters were created with a mean size of 87 diseases. We validate the clusters quantitatively via semantic similarity based on the Orphanet Rare Disease Ontology. In addition, the clusters were analyzed for enrichment of associated genes, revealing that the enriched genes within clusters are highly related. DISCUSSION: We demonstrate that node embeddings are an effective method for clustering diseases within a heterogenous KG. Semantically similar diseases and relevant enriched genes have been uncovered within the clusters. Connections between disease clusters and drugs are enumerated for follow-up efforts. CONCLUSION: We lay out a method for clustering rare diseases using graph node embeddings. We develop an easy-to-maintain pipeline that can be updated when new data on rare diseases emerges. The embeddings themselves can be paired with other representation learning methods for other data types, such as drugs, to address other predictive modeling problems.

Machine learning using institution-specific multi-modal electronic health records improves mortality risk prediction for cardiac surgery patients.

Background: The Society of Thoracic Surgeons risk scores are widely used to assess risk of morbidity and mortality in specific cardiac surgeries but may not perform optimally in all patients. In a cohort of patients undergoing cardiac surgery, we developed a data-driven, institution-specific machine learning-based model inferred from multi-modal electronic health records and compared the performance with the Society of Thoracic Surgeons models. Methods: All adult patients undergoing cardiac surgery between 2011 and 2016 were included. Routine electronic health record administrative, demographic, clinical, hemodynamic, laboratory, pharmacological, and procedural data features were extracted. The outcome was postoperative mortality. The database was randomly split into training (development) and test (evaluation) cohorts. Models developed using 4 classification algorithms were compared using 6 evaluation metrics. The performance of the final model was compared with the Society of Thoracic Surgeons models for 7 index surgical procedures. Results: A total of 6392 patients were included and described by 4016 features. Overall mortality was 3.0% (n = 193). The XGBoost algorithm using only features with no missing data (336 features) yielded the best-performing predictor. When applied to the test set, the predictor performed well (F-measure = 0.775; precision = 0.756; recall = 0.795; accuracy = 0.986; area under the receiver operating characteristic curve = 0.978; area under the precision-recall curve = 0.804). eXtreme Gradient Boosting consistently demonstrated improved performance over the Society of Thoracic Surgeons models when evaluated on index procedures within the test set. Conclusions: Machine learning models using institution-specific multi-modal electronic health records may improve performance in predicting mortality for individual patients undergoing cardiac surgery compared with the standard-of-care, population-derived Society of Thoracic Surgeons models. Institution-specific models may provide insights complementary to population-derived risk predictions to aid patient-level decision making.

Preexisting Autoimmunity Is Associated With Increased Severity of Coronavirus Disease 2019: A Retrospective Cohort Study Using Data From the National COVID Cohort Collaborative (N3C).

BACKGROUND: Identifying individuals with a higher risk of developing severe coronavirus disease 2019 (COVID-19) outcomes will inform targeted and more intensive clinical monitoring and management. To date, there is mixed evidence regarding the impact of preexisting autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure on developing severe COVID-19 outcomes. METHODS: A retrospective cohort of adults diagnosed with COVID-19 was created in the National COVID Cohort Collaborative enclave. Two outcomes, life-threatening disease and hospitalization, were evaluated by using logistic regression models with and without adjustment for demographics and comorbidities. RESULTS: Of the 2 453 799 adults diagnosed with COVID-19, 191 520 (7.81%) had a preexisting AID diagnosis and 278 095 (11.33%) had a preexisting IS exposure. Logistic regression models adjusted for demographics and comorbidities demonstrated that individuals with a preexisting AID (odds ratio [OR], 1.13; 95% confidence interval [CI]: 1.09-1.17; P < .001), IS exposure (OR, 1.27; 95% CI: 1.24-1.30; P < .001), or both (OR, 1.35; 95% CI: 1.29-1.40; P < .001) were more likely to have a life-threatening disease. These results were consistent when hospitalization was evaluated. A sensitivity analysis evaluating specific IS revealed that tumor necrosis factor inhibitors were protective against life-threatening disease (OR, 0.80; 95% CI: .66-.96; P = .017) and hospitalization (OR, 0.80; 95% CI: .73-.89; P < .001). CONCLUSIONS: Patients with preexisting AID, IS exposure, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.

Precision information extraction for rare disease epidemiology at scale.

BACKGROUND: The United Nations recently made a call to address the challenges of an estimated 300 million persons worldwide living with a rare disease through the collection, analysis, and dissemination of disaggregated data. Epidemiologic Information (EI) regarding prevalence and incidence data of rare diseases is sparse and current paradigms of identifying, extracting, and curating EI rely upon time-intensive, error-prone manual processes. With these limitations, a clear understanding of the variation in epidemiology and outcomes for rare disease patients is hampered. This challenges the public health of rare diseases patients through a lack of information necessary to prioritize research, policy decisions, therapeutic development, and health system allocations. METHODS: In this study, we developed a newly curated epidemiology corpus for Named Entity Recognition (NER), a deep learning framework, and a novel rare disease epidemiologic information pipeline named EpiPipeline4RD consisting of a web interface and Restful API. For the corpus creation, we programmatically gathered a representative sample of rare disease epidemiologic abstracts, utilized weakly-supervised machine learning techniques to label the dataset, and manually validated the labeled dataset. For the deep learning framework development, we fine-tuned our dataset and adapted the BioBERT model for NER. We measured the performance of our BioBERT model for epidemiology entity recognition quantitatively with precision, recall, and F1 and qualitatively through a comparison with Orphanet. We demonstrated the ability for our pipeline to gather, identify, and extract epidemiology information from rare disease abstracts through three case studies. RESULTS: We developed a deep learning model to extract EI with overall F1 scores of 0.817 and 0.878, evaluated at the entity-level and token-level respectively, and which achieved comparable qualitative results to Orphanet's collection paradigm. Additionally, case studies of the rare diseases Classic homocystinuria, GRACILE syndrome, Phenylketonuria demonstrated the adequate recall of abstracts with epidemiology information, high precision of epidemiology information extraction through our deep learning model, and the increased efficiency of EpiPipeline4RD compared to a manual curation paradigm. CONCLUSIONS: EpiPipeline4RD demonstrated high performance of EI extraction from rare disease literature to augment manual curation processes. This automated information curation paradigm will not only effectively empower development of the NIH Genetic and Rare Diseases Information Center (GARD), but also support the public health of the rare disease community.

Pre-existing autoimmunity is associated with increased severity of COVID-19: A retrospective cohort study using data from the National COVID Cohort Collaborative (N3C).

Importance: Identifying individuals with a higher risk of developing severe COVID-19 outcomes will inform targeted or more intensive clinical monitoring and management. Objective: To examine, using data from the National COVID Cohort Collaborative (N3C), whether patients with pre-existing autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure are at a higher risk of developing severe COVID-19 outcomes. Design setting and participants: A retrospective cohort of 2,453,799 individuals diagnosed with COVID-19 between January 1 st , 2020, and June 30 th , 2022, was created from the N3C data enclave, which comprises data of 15,231,849 patients from 75 USA data partners. Patients were stratified as those with/without a pre-existing diagnosis of AID and/or those with/without exposure to IS prior to COVID-19. Main outcomes and measures: Two outcomes of COVID-19 severity, derived from the World Health Organization severity score, were defined, namely life-threatening disease and hospitalization. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using logistic regression models with and without adjustment for demographics (age, BMI, gender, race, ethnicity, smoking status), and comorbidities (cardiovascular disease, dementia, pulmonary disease, liver disease, type 2 diabetes mellitus, kidney disease, cancer, and HIV infection). Results: In total, 2,453,799 (16.11% of the N3C cohort) adults (age> 18 years) were diagnosed with COVID-19, of which 191,520 (7.81%) had a prior AID diagnosis, and 278,095 (11.33%) had a prior IS exposure. Logistic regression models adjusted for demographic factors and comorbidities demonstrated that individuals with a prior AID (OR = 1.13, 95% CI 1.09 - 1.17; p =2.43E-13), prior exposure to IS (OR= 1.27, 95% CI 1.24 - 1.30; p =3.66E-74), or both (OR= 1.35, 95% CI 1.29 - 1.40; p =7.50E-49) were more likely to have a life-threatening COVID-19 disease. These results were confirmed after adjusting for exposure to antivirals and vaccination in a cohort subset with COVID-19 diagnosis dates after December 2021 (AID OR = 1.18, 95% CI 1.02 - 1.36; p =2.46E-02; IS OR= 1.60, 95% CI 1.41 - 1.80; p =5.11E-14; AID+IS OR= 1.93, 95% CI 1.62 - 2.30; p =1.68E-13). These results were consistent when evaluating hospitalization as the outcome and also when stratifying by race and sex. Finally, a sensitivity analysis evaluating specific IS revealed that TNF inhibitors were protective against life-threatening disease (OR = 0.80, 95% CI 0.66-0.96; p =1.66E-2) and hospitalization (OR = 0.80, 95% CI 0.73 - 0.89; p =1.06E-05). Conclusions and Relevance: Patients with pre-existing AID, exposure to IS, or both are more likely to have a life-threatening disease or hospitalization. These patients may thus require tailored monitoring and preventative measures to minimize negative consequences of COVID-19.

Whole cell response to receptor stimulation involves many deep and distributed subcellular biochemical processes.

Neurite outgrowth is an integrated whole cell response triggered by the cannabinoid-1 receptor. We sought to identify the many different biochemical pathways that contribute to this whole cell response. To understand underlying mechanisms, we identified subcellular processes (SCPs) composed of one or more biochemical pathways and their interactions required for this response. Differentially expressed genes and proteins were obtained from bulk transcriptomics and proteomic analysis of extracts from cells stimulated with a cannabinoid-1 receptor agonist. We used these differentially expressed genes and proteins to build networks of interacting SCPs by combining the expression data with prior pathway knowledge. From these SCP networks, we identified additional genes that when ablated, experimentally validated the SCP involvement in neurite outgrowth. Our experiments and informatics modeling allowed us to identify diverse SCPs such as those involved in pyrimidine metabolism, lipid biosynthesis, and mRNA splicing and stability, along with more predictable SCPs such as membrane vesicle transport and microtubule dynamics. We find that SCPs required for neurite outgrowth are widely distributed among many biochemical pathways required for constitutive cellular functions, several of which are termed 'deep', since they are distal to signaling pathways and the key SCPs directly involved in extension of the neurite. In contrast, 'proximal' SCPs are involved in microtubule growth and membrane vesicle transport dynamics required for neurite outgrowth. From these bioinformatics and dynamical models based on experimental data, we conclude that receptor-mediated regulation of subcellular functions for neurite outgrowth is both distributed, that is, involves many different biochemical pathways, and deep.

Functional Effects of Cardiomyocyte Injury in COVID-19.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System show that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrated cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of interleukins (ILs) with clinical findings related to laboratory values in COVID-19 patients to identify plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes from healthy human subjects with SARS-CoV-2 in the absence and presence of IL-6 and IL-1ß. Infection resulted in increased numbers of multinucleated cells. Interleukin treatment and infection resulted in disorganization of myofibrils, extracellular release of troponin I, and reduced and erratic beating. Infection resulted in decreased expression of mRNA encoding key proteins of the cardiomyocyte contractile apparatus. Although interleukins did not increase the extent of infection, they increased the contractile dysfunction associated with viral infection of cardiomyocytes, resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health System show that a significant portion of COVID-19 patients without history of heart disease have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection might underlie heart disease in COVID-19 patients. IMPORTANCE SARS-CoV-2 infects multiple organs, including the heart. Analyses of hospitalized patients show that a substantial number without prior indication of heart disease or comorbidities show significant injury to heart tissue, assessed by increased levels of troponin in blood. We studied the cell biological and physiological effects of virus infection of healthy human iPSC-derived cardiomyocytes in culture. Virus infection with interleukins disorganizes myofibrils, increases cell size and the numbers of multinucleated cells, and suppresses the expression of proteins of the contractile apparatus. Viral infection of cardiomyocytes in culture triggers release of troponin similar to elevation in levels of COVID-19 patients with heart disease. Viral infection in the presence of interleukins slows down and desynchronizes the beating of cardiomyocytes in culture. The cell-level physiological changes are similar to decreases in left ventricular ejection seen in imaging of patients' hearts. These observations suggest that direct injury to heart tissue by virus can be one underlying cause of heart disease in COVID-19.

A library of induced pluripotent stem cells from clinically well-characterized, diverse healthy human individuals.

A library of well-characterized human induced pluripotent stem cell (hiPSC) lines from clinically healthy human subjects could serve as a useful resource of normal controls for in vitro human development, disease modeling, genotype-phenotype association studies, and drug response evaluation. We report generation and extensive characterization of a gender-balanced, racially/ethnically diverse library of hiPSC lines from 40 clinically healthy human individuals who range in age from 22 to 61 years. The hiPSCs match the karyotype and short tandem repeat identities of their parental fibroblasts, and have a transcription profile characteristic of pluripotent stem cells. We provide whole-genome sequencing data for one hiPSC clone from each individual, genomic ancestry determination, and analysis of mendelian disease genes and risks. We document similar transcriptomic profiles, single-cell RNA-sequencing-derived cell clusters, and physiology of cardiomyocytes differentiated from multiple independent hiPSC lines. This extensive characterization makes this hiPSC library a valuable resource for many studies on human biology.

Physiology of cardiomyocyte injury in COVID-19.

COVID-19 affects multiple organs. Clinical data from the Mount Sinai Health System shows that substantial numbers of COVID-19 patients without prior heart disease develop cardiac dysfunction. How COVID-19 patients develop cardiac disease is not known. We integrate cell biological and physiological analyses of human cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) infected with SARS-CoV-2 in the presence of interleukins, with clinical findings, to investigate plausible mechanisms of cardiac disease in COVID-19 patients. We infected hiPSC-derived cardiomyocytes, from healthy human subjects, with SARS-CoV-2 in the absence and presence of interleukins. We find that interleukin treatment and infection results in disorganization of myofibrils, extracellular release of troponin-I, and reduced and erratic beating. Although interleukins do not increase the extent, they increase the severity of viral infection of cardiomyocytes resulting in cessation of beating. Clinical data from hospitalized patients from the Mount Sinai Health system show that a significant portion of COVID-19 patients without prior history of heart disease, have elevated troponin and interleukin levels. A substantial subset of these patients showed reduced left ventricular function by echocardiography. Our laboratory observations, combined with the clinical data, indicate that direct effects on cardiomyocytes by interleukins and SARS-CoV-2 infection can underlie the heart disease in COVID-19 patients.

Clinical features of COVID-19 mortality: development and validation of a clinical prediction model.

Background: The COVID-19 pandemic has affected millions of individuals and caused hundreds of thousands of deaths worldwide. Predicting mortality among patients with COVID-19 who present with a spectrum of complications is very difficult, hindering the prognostication and management of the disease. We aimed to develop an accurate prediction model of COVID-19 mortality using unbiased computational methods, and identify the clinical features most predictive of this outcome. Methods: In this prediction model development and validation study, we applied machine learning techniques to clinical data from a large cohort of patients with COVID-19 treated at the Mount Sinai Health System in New York City, NY, USA, to predict mortality. We analysed patient-level data captured in the Mount Sinai Data Warehouse database for individuals with a confirmed diagnosis of COVID-19 who had a health system encounter between March 9 and April 6, 2020. For initial analyses, we used patient data from March 9 to April 5, and randomly assigned (80:20) the patients to the development dataset or test dataset 1 (retrospective). Patient data for those with encounters on April 6, 2020, were used in test dataset 2 (prospective). We designed prediction models based on clinical features and patient characteristics during health system encounters to predict mortality using the development dataset. We assessed the resultant models in terms of the area under the receiver operating characteristic curve (AUC) score in the test datasets. Findings: Using the development dataset (n=3841) and a systematic machine learning framework, we developed a COVID-19 mortality prediction model that showed high accuracy (AUC=0·91) when applied to test datasets of retrospective (n=961) and prospective (n=249) patients. This model was based on three clinical features: patient's age, minimum oxygen saturation over the course of their medical encounter, and type of patient encounter (inpatient vs outpatient and telehealth visits). Interpretation: An accurate and parsimonious COVID-19 mortality prediction model based on three features might have utility in clinical settings to guide the management and prognostication of patients affected by this disease. External validation of this prediction model in other populations is needed. Funding: National Institutes of Health.

Clinical predictors of COVID-19 mortality.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has affected over millions of individuals and caused hundreds of thousands of deaths worldwide. It can be difficult to accurately predict mortality among COVID-19 patients presenting with a spectrum of complications, hindering the prognostication and management of the disease. METHODS: We applied machine learning techniques to clinical data from a large cohort of 5,051 COVID-19 patients treated at the Mount Sinai Health System in New York City, the global COVID-19 epicenter, to predict mortality. Predictors were designed to classify patients into Deceased or Alive mortality classes and were evaluated in terms of the area under the receiver operating characteristic (ROC) curve (AUC score). FINDINGS: Using a development cohort (n=3,841) and a systematic machine learning framework, we identified a COVID-19 mortality predictor that demonstrated high accuracy (AUC=0.91) when applied to test sets of retrospective (n= 961) and prospective (n=249) patients. This mortality predictor was based on five clinical features: age, minimum O2 saturation during encounter, type of patient encounter (inpatient vs. various types of outpatient and telehealth encounters), hydroxychloroquine use, and maximum body temperature. INTERPRETATION: An accurate and parsimonious COVID-19 mortality predictor based on five features may have utility in clinical settings to guide the management and prognostication of patients affected by this disease.

Dynamic balance between vesicle transport and microtubule growth enables neurite outgrowth.

Whole cell responses involve multiple subcellular processes (SCPs). To understand how balance between SCPs controls the dynamics of whole cell responses we studied neurite outgrowth in rat primary cortical neurons in culture. We used a combination of dynamical models and experiments to understand the conditions that permitted growth at a specified velocity and when aberrant growth could lead to the formation of dystrophic bulbs. We hypothesized that dystrophic bulb formation is due to quantitative imbalances between SCPs. Simulations predict redundancies between lower level sibling SCPs within each type of high level SCP. In contrast, higher level SCPs, such as vesicle transport and exocytosis or microtubule growth characteristic of each type need to be strictly coordinated with each other and imbalances result in stalling of neurite outgrowth. From these simulations, we predicted the effect of changing the activities of SCPs involved in vesicle exocytosis or microtubule growth could lead to formation of dystrophic bulbs. siRNA ablation experiments verified these predictions. We conclude that whole cell dynamics requires balance between the higher-level SCPs involved and imbalances can terminate whole cell responses such as neurite outgrowth.