The Integrated Medical Model: A Probabilistic Simulation Model Predicting In-Flight Medical Risks

The Integrated Medical Model (IMM) is a probabilistic model that uses simulation to predict mission medical risk. Given a specific mission and crew scenario, medical events are simulated using Monte Carlo methodology to provide estimates of resource utilization, probability of evacuation, probability of loss of crew, and the amount of mission time lost due to illness. Mission and crew scenarios are defined by mission length, extravehicular activity (EVA) schedule, and crew characteristics including: sex, coronary artery calcium score, contacts, dental crowns, history of abdominal surgery, and EVA eligibility. The Integrated Medical Evidence Database (iMED) houses the model inputs for one hundred medical conditions using in-flight, analog, and terrestrial medical data. Inputs include incidence, event durations, resource utilization, and crew functional impairment. Severity of conditions is addressed by defining statistical distributions on the dichotomized best and worst-case scenarios for each condition. The outcome distributions for conditions are bounded by the treatment extremes of the fully treated scenario in which all required resources are available and the untreated scenario in which no required resources are available. Upon occurrence of a simulated medical event, treatment availability is assessed, and outcomes are generated depending on the status of the affected crewmember at the time of onset, including any pre-existing functional impairments or ongoing treatment of concurrent conditions. The main IMM outcomes, including probability of evacuation and loss of crew life, time lost due to medical events, and resource utilization, are useful in informing mission planning decisions. To date, the IMM has been used to assess mission-specific risks with and without certain crewmember characteristics, to determine the impact of eliminating certain resources from the mission medical kit, and to design medical kits that maximally benefit crew health while meeting mass and volume constraints

The Integrated Medical Model: A Probabilistic Simulation Model for Predicting In-Flight Medical Risks

The Integrated Medical Model (IMM) is a probabilistic model that uses simulation to predict mission medical risk. Given a specific mission and crew scenario, medical events are simulated using Monte Carlo methodology to provide estimates of resource utilization, probability of evacuation, probability of loss of crew, and the amount of mission time lost due to illness. Mission and crew scenarios are defined by mission length, extravehicular activity (EVA) schedule, and crew characteristics including: sex, coronary artery calcium score, contacts, dental crowns, history of abdominal surgery, and EVA eligibility. The Integrated Medical Evidence Database (iMED) houses the model inputs for one hundred medical conditions using in-flight, analog, and terrestrial medical data. Inputs include incidence, event durations, resource utilization, and crew functional impairment. Severity of conditions is addressed by defining statistical distributions on the dichotomized best and worst-case scenarios for each condition. The outcome distributions for conditions are bounded by the treatment extremes of the fully treated scenario in which all required resources are available and the untreated scenario in which no required resources are available. Upon occurrence of a simulated medical event, treatment availability is assessed, and outcomes are generated depending on the status of the affected crewmember at the time of onset, including any pre-existing functional impairments or ongoing treatment of concurrent conditions. The main IMM outcomes, including probability of evacuation and loss of crew life, time lost due to medical events, and resource utilization, are useful in informing mission planning decisions. To date, the IMM has been used to assess mission-specific risks with and without certain crewmember characteristics, to determine the impact of eliminating certain resources from the mission medical kit, and to design medical kits that maximally benefit crew health while meeting mass and volume constraints

Enabling Space Exploration Medical System Development Using a Tool Ecosystem

The NASA Human Research Program's (HRP) Exploration Medical Capability (ExMC) Element is utilizing a Model Based Systems Engineering (MBSE) approach to enhance the development of systems engineering products that will be used to advance medical system designs for exploration missions beyond Low Earth Orbit. In support of future missions, the team is capturing content such as system behaviors, functional decompositions, architecture, system requirements and interfaces, and recommendations for clinical capabilities and resources in Systems Modeling Language (SysML) models. As these products mature, SysML models provide a way for ExMC to capture relationships among the various products, which includes supporting more integrated and multi-faceted views of future medical systems. In addition to using SysML models, HRP and ExMC are developing supplementary tools to support two key functions: 1) prioritizing current and future research activities for exploration missions in an objective manner; and 2) enabling risk-informed and evidence-based trade space analysis for future space vehicles, missions, and systems. This paper will discuss the long-term HRP and ExMC vision for the larger ecosystem of tools, which include dynamic Probabilistic Risk Assessment (PRA) capabilities, additional SysML models, a database of system component options, and data visualizations. It also includes a review of an initial Pilot Project focused on enabling medical system trade studies utilizing data that is coordinated across tools for consistent outputs (e.g., mission risk metrics that are associated with medical system mass values and medical conditions addressed). This first Pilot Project demonstrated successful operating procedures and integration across tools. Finally, the paper will also cover a second Pilot Project that utilizes tool enhancements such as medical system optimization capabilities, post-processing, and visualization of generated data for subject matter expert review, and increased integration amongst the tools themselves

Validation of the NASA Integrated Medical Model: a Space Flight Medical Risk Prediction Tool

The Human Research Program funded the development of the Integrated Medical Model (IMM) to quantify the medical component of overall mission risk. The IMM uses Monte Carlo simulation methodology, incorporating space flight and ground medical data, to estimate the probability of mission medical outcomes and resource utilization. To determine the credibility of IMM output, the IMM project team completed two validation studies that compared IMM predicted output to observed medical events from a selection of Shuttle Transportation System (STS) and International Space Station (ISS) missions. The validation study results showed that the IMM underpredicted the occurrence of ~10% of the modeled medical conditions for the STS missions and overpredicted ~20% of the modeled medical conditions for the ISS missions. These findings imply that the strength of IMM predictions to inform decisions depends on simulated mission specifications including length. This discrepancy could result from medical recording differences between ISS and STS that possibly influence observed incidence rates, IMM combining all "mission type" data as constant occurrence rate or fixed proportion across both mission types, misspecification of symptoms to conditions, and gaps in the literature informing the model. Some of these issues will be alleviated by updating the IMM source data through incorporation of the observed validation data

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Analysis of Shared Heritability in Common Disorders of the Brain

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology