Paradigm For Translational Research Research Articles

Advances in the Clinical Application of High-throughput Proteomics.

High-throughput proteomics has become an exciting field and a potential frontier of modern medicine since the early 2000s. While significant progress has been made in the technical aspects of the field, translating proteomics to clinical applications has been challenging. This review summarizes recent advances in clinical applications of high-throughput proteomics and discusses the associated challenges, advantages, and future directions. We focus on research progress and clinical applications of high-throughput proteomics in breast cancer, bladder cancer, laryngeal squamous cell carcinoma, gastric cancer, colorectal cancer, and coronavirus disease 2019. The future application of high-throughput proteomics will face challenges such as varying protein properties, limitations of statistical modeling, technical and logistical difficulties in data deposition, integration, and harmonization, as well as regulatory requirements for clinical validation and considerations. However, there are several noteworthy advantages of high-throughput proteomics, including the identification of novel global protein networks, the discovery of new proteins, and the synergistic incorporation with other omic data. We look forward to participating in and embracing future advances in high-throughput proteomics, such as proteomics-based single-cell biology and its clinical applications, individualized proteomics, pathology informatics, digital pathology, and deep learning models for high-throughput proteomics. Several new proteomic technologies are noteworthy, including data-independent acquisition mass spectrometry, nanopore-based proteomics, 4-D proteomics, and secondary ion mass spectrometry. In summary, we believe high-throughput proteomics will drastically shift the paradigm of translational research, clinical practice, and public health in the near future.

Dynamics of cerebral blood volume during and after middle cerebral artery occlusion in rats – Comparison between ultrafast ultrasound and dynamic susceptibility contrast-enhanced MRI measurements

Tomographic perfusion imaging techniques are integral to translational stroke research paradigms that advance our understanding of the disease. Functional ultrasound (fUS) is an emerging technique that informs on cerebral blood volume (CBV) through ultrasensitive Doppler and flow velocity (CBFv) through ultrafast localization microscopy. It is not known how experimental results compare with a classical CBV-probing technique such as dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI). To that end, we assessed hemodynamics based on uUS (n = 6) or DSC-MRI (n = 7) before, during and up to three hours after 90-minute filament-induced middle cerebral artery occlusion (MCAO) in rats. Recanalization was followed by a brief hyperperfusion response, after which CBV and CBFv temporarily normalized but progressively declined after one hour in the lesion territory. DSC-MRI data corroborated the incomplete restoration of CBV after recanalization, which may have been caused by the free-breathing anesthetic regimen. During occlusion, MCAO-induced hypoperfusion was more discrepant between either technique, likely attributable to artefactual signal mechanisms related to slow flow, and processing algorithms employed for either technique. In vivo uUS- and DSC-MRI-derived measures of CBV enable serial whole-brain assessment of post-stroke hemodynamics, but readouts from both techniques need to be interpreted cautiously in situations of very low blood flow.

Refocusing the Translational Research Paradigm on Problem-solving and Community Engagement: Recommendations from a Critical Review of the Literature

Refocusing the Translational Research Paradigm on Problem-solving and Community Engagement: Recommendations from a Critical Review of the Literature

Using a translational research paradigm to investigate dietary intake of fruit juice on per- and polyfluoroalkyl substances (PFAS) concentrations

BACKGROUND AND AIM: Certain fruit juices, such as apple juice (AJ), contain bioactive molecules that can impair intestinal drug absorption through inhibition of transporter Organic Anion Transporting Polypeptide 2B1 (OATP2B1). Because some PFAS have been shown to be OATP2B1 substrates, we used a translational research paradigm to explore our hypothesis that higher fruit juice intake is associated with lower PFAS concentrations. METHODS: Female C57Bl/6 mice were administered perfluorooctane sulfonic acid (PFOS, 5 mg/kg) in buffer or in 4x AJ concentrate, with blood and tissues collected 5 hours after administration. Tissue PFOS was extracted and quantified by LC-MS. Epidemiologic analysis was conducted on 345 adolescents aged 12-19 years and 1,458 adults aged 20-80 years using the National Health and Nutrition Examination Study (NHANES), 2013 - 2014 cycle. Pure (100%) fruit juice intake was assessed by 24h dietary recall. Log-2 transformed serum concentrations of PFOS, perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS) were evaluated. Multivariable regression models were used to assess changes in PFAS concentrations in relation to dietary intake of juice, adjusting for covariates. RESULTS:In mice, 4x AJ co-administration decreased PFOS concentrations in blood, liver, kidney, and brain 5 hours after administration, indicating that 4x AJ can inhibit or delay PFOS absorption. Intake of pure fruit juice more than 1 time in the previous 24h was associated with a 15% (95%CI: -28%, -1%) reduction in serum PFOA concentration compared with no intake of juice among adolescents. No associations were observed between fruit juice intake and PFAS concentrations in adults. CONCLUSIONS:Combining experimental and epidemiological data, fruit juice consumption might lower PFAS burden. More research is needed to elucidate the effect of fruit juice consumption on PFAS concentrations in humans across age groups. KEYWORDS: PFAS, juice, translational, exposure reduction

3519 Community Engagement And Health Disparities In Clinical And Translational Research Course: A Joint Academic Institution Approach

OBJECTIVES/SPECIFIC AIMS: Current translational research moves beyond bench to bedside and includes translating scientific evidence to clinical practice and into the community settings (T1-T5). This progression is dynamic, involving patient-physician, community, and academic organizational structures and translational strategies. However, basic and clinician scientists are often unprepared and/or ill equipped to successfully conduct community-engaged research which may aid in more efficient translation of their research findings. The recognized need for such training was the impetus for our course which was originally designed and implemented through the innovative and sustainable joint academic-community partnerships of Morehouse School of Medicine and Emory University with the support of Georgia Institute of Technology. Since that time the course has evolved with the recently added partner, University of Georgia. METHODS/STUDY POPULATION: Initially developed and implemented in 2008, the course continues through the Georgia Clinical and Translational Science Alliance, Community Engagement and Research Program (GaCTSA/CERP), a Clinical Translational Science Award (CTSA) (UL1TR002378). The course is an introduction to community-engaged research concepts/methods. This includes behavioral science; community engagement principles; clinical translational research partnerships; and strategies in planning, implementing, evaluating, and disseminating community-engaged research to address health disparities. The course is open to the four GaCTSA academic institutions’ faculty, MD, PhD, MS in Clinical Research, and the Graduate Certificate in Translational Science students. RESULTS/ANTICIPATED RESULTS: Students received scholarly and hands-on training in community engaged research through faculty- and community member-led didactic lectures/interactions, team science activities, and a final assignment involving work with a community-based organization. From 2008-2017 over 230 students have matriculated through this course and many are now involved in community-engaged translational research. Most students in the class were MD/PhD students (33%), however 21% were junior faculty, attending physicians (21%), or fellows/residents/ postdocs (15%). Evaluations over the years indicate that most students were unware of Community-Based Participatory or community-engagement strategies for conducting translational research. DISCUSSION/SIGNIFICANCE OF IMPACT: Effective application of community-engaged translational research requires essential skills training to facilitate the translational research paradigm. Translational researchers, at any stage, will benefit from understanding the entire translational research process and the importance of quickly bringing research advances to patients and the community.

Evolution of The Qatar Trauma System: The Journey from Inception to Verification.

Traumatic injuries accounted for substantial burden of morbidity and mortality (M and M) worldwide. Despite better socioeconomic conditions and living standards, the incidence of trauma is rising in the Eastern Mediterranean Region (EMR). Road traffic injuries are the leading cause of the high fatality rate in young economically productive adults in our region. The provision of trauma care at high-volume, accredited trauma center by a team of dedicated full-time professional health-care providers has been shown to improve the quality of care and the outcomes for trauma victims. With persistent hard work and effective leadership, in Qatar, the Trauma Section has evolved into a well-reputed and internationally recognized Center of Excellence in Trauma Care, Hamad Level 1 Trauma Center. In 2014, Qatar Trauma System was accredited with Trauma Distinction Award by the Accreditation Canada International, for high-quality trauma care of severely injured patients; first in the Middle East. The Hamad Trauma Center is committed to the advancement of trauma care in different aspects right from the immediate prehospital care to the subsequent hospital-based care, involving diagnosis, treatment, support, rehabilitation, and community reintegration of the patients and injury prevention. Our trauma system has gradually embedded with a structured and matured research unit with dedicated clinicians and academic researchers. The trauma team embodies the 21st-century paradigm of translational research and injury prevention by going well beyond the bedside, out into the populations that need it most. The trauma system's future vision relies on the evidence-based health-care service and better outcomes; state-of-the-art infrastructure and multidimensional collaborations with health care and governmental services to minimize the burden of M and M caused by traumatic injury in the State of Qatar and to fulfill the population health enhancement strategy.

Social aversive conditioning in youth at clinical high risk for psychosis and with psychosis: An ERP study

BackgroundSocial cognition and emotion processing are compromised in schizophrenia. Disruptions in these domains may also be present during the psychosis-risk state. Aversive conditioning is an established translational research paradigm to investigate affective reactivity and learning. Using an aversive conditioning ERP paradigm with social cues, we examined whether psychosis patients and at-risk youths differentially respond to aversively conditioned faces. MethodsParticipants (ages 10–30) were enrolled into three demographically-matched groups: clinical risk for psychosis (CR, n = 32), psychosis (PS, n = 26), and healthy control (HC, n = 33). EEGs were recorded during a delay aversive conditioning task in which three neutral faces were paired with an aversive tone at 100%, 50% and 0% contingencies. Analysis focused on group differences in ERP peaks representing visual processing (occipital P120), emotional valence (frontal VPP), and directed attention (parietal-occipital P300), for dimensions of aversiveness (100% vs. 0%) and unpredictability (50% vs. 100% + 0%). ResultsHC, but not CR or PS, showed increased P300 amplitude to aversive vs. non-aversive conditioned stimuli. CR, but not PS or HC, showed increased VPP amplitude to unpredictable vs. predictable stimuli. ConclusionsPS and CR both fail to allocate appropriate salience to social cues that are predictably aversive. CR, but not PS exhibit heightened emotional reactivity to social cues that are of uncertain salience. Clinical risk for schizophrenia may involve neural abnormalities distinct from both healthy and fully-established disease states.

Drug Resistance in HER2-Positive Breast Cancer Brain Metastases: Blame the Barrier or the Brain?

The brain is the most common site of first metastasis for patients with HER2-positive breast cancer treated with HER2-targeting drugs. However, the development of effective therapies for breast cancer brain metastases (BCBM) is limited by an incomplete understanding of the mechanisms governing drug sensitivity in the central nervous system. Pharmacodynamic data from patients and in vivo models suggest that inadequate drug penetration across the "blood-tumor" barrier is not the whole story. Using HER2-positive BCBMs as a case study, we highlight recent data from orthotopic brain metastasis models that implicate brain-specific drug resistance mechanisms in BCBMs and suggest a translational research paradigm to guide drug development for treatment of BCBMs. Clin Cancer Res; 24(8); 1795-804. ©2018 AACR.

Utility of the Hebb-Williams Maze Paradigm for Translational Research in Fragile X Syndrome: A Direct Comparison of Mice and Humans.

To generate meaningful information, translational research must employ paradigms that allow extrapolation from animal models to humans. However, few studies have evaluated translational paradigms on the basis of defined validation criteria. We outline three criteria for validating translational paradigms. We then evaluate the Hebb–Williams maze paradigm (Hebb and Williams, 1946; Rabinovitch and Rosvold, 1951) on the basis of these criteria using Fragile X syndrome (FXS) as model disease. We focused on this paradigm because it allows direct comparison of humans and animals on tasks that are behaviorally equivalent (criterion #1) and because it measures spatial information processing, a cognitive domain for which FXS individuals and mice show impairments as compared to controls (criterion #2). We directly compared the performance of affected humans and mice across different experimental conditions and measures of behavior to identify which conditions produce comparable patterns of results in both species. Species differences were negligible for Mazes 2, 4, and 5 irrespective of the presence of visual cues, suggesting that these mazes could be used to measure spatial learning in both species. With regards to performance on the first trial, which reflects visuo-spatial problem solving, Mazes 5 and 9 without visual cues produced the most consistent results. We conclude that the Hebb–Williams mazes paradigm has the potential to be utilized in translational research to measure comparable cognitive functions in FXS humans and animals (criterion #3).

The Current Trend of the Translational Research Paradigm.

The translational research paradigm is a process of discovering basic science concepts and applying the knowledge in clinical practice, aiming to improve patient care. The stages involved in the paradigm form a complex network of shared knowledge amongst research collaborators, including patients. This nature of the paradigm allows those involved to work together effectively. However, the translational research paradigm is often overlooked by many scientists, educators, and research institutions. Hence, a large amount of comprehensive and hugely invested research projects fail to make a scientific impact. We aim to outline and describe this paradigm in order to aid in the successful translation of effective research.

Defining Disease, Diagnosis, and Translational Medicine within a Homeostatic Perturbation Paradigm: The National Institutes of Health Undiagnosed Diseases Program Experience.

Traditionally, the use of genomic information for personalized medical decisions relies on prior discovery and validation of genotype–phenotype associations. This approach constrains care for patients presenting with undescribed problems. The National Institutes of Health (NIH) Undiagnosed Diseases Program (UDP) hypothesized that defining disease as maladaptation to an ecological niche allows delineation of a logical framework to diagnose and evaluate such patients. Herein, we present the philosophical bases, methodologies, and processes implemented by the NIH UDP. The NIH UDP incorporated use of the Human Phenotype Ontology, developed a genomic alignment strategy cognizant of parental genotypes, pursued agnostic biochemical analyses, implemented functional validation, and established virtual villages of global experts. This systematic approach provided a foundation for the diagnostic or non-diagnostic answers provided to patients and serves as a paradigm for scalable translational research.

Self-Regulation and Psychopathology: Toward an Integrative Translational Research Paradigm.

This article presents a general framework in which different manifestations of psychopathology can be conceptualized as dysfunctions in one or more mechanisms of self-regulation, defined as the ongoing process of managing personal goal pursuit in the face of internal, interpersonal, and environmental forces that would derail it. The framework is based on the assertion that self-regulation is a critical locus for the proximal influence on motivation, cognition, emotion, and behavior of more distal factors such as genetics, temperament, socialization history, and neurophysiology. Psychological theories of self-regulation are ideal platforms from which to integrate the study of self-regulation both within and across traditional disciplines. This article has two related goals: to elucidate how the construct of self-regulation provides a unique conceptual platform for the study of psychopathology and to illustrate that platform by presenting our research on depression as an example.

T034 Transcranial brain stimulation in psychiatry – translational research towards treatment?

Objectives Transcranial brain stimulation (TBS) techniques are promising as therapeutic interventions in psychiatry and few large randomized controlled trials (e.g. in depressive disorders) have opened the field for wider clinical applications. In addition, an enormous set of experimental data for TBS is available from human neurophysiology and cognitive neuroscience research. TBS has been investigated in cellular and animal models, though studies are not as numerous compared to research in humans. With this background, coordinated translational research is a neglected field and particularly promising in order to transfer preclinical knowledge to clinical applications and could be strengthened by establishing specific coordinated research programs. The German Center of Brain Stimulation (GCBS, www.gcbs.network ) funded by the German Federal Ministry of Research and Education (BMBF) since 2015 set out on this endeavor. Methods & results Three examples from the GCBS will be given to illustrate the added value of coordinated research in this field: (1) reverse translation, i.e. establishing complementary animal models for TBS protocols in humans and investigating their mechanisms of action, (2) The effect of transcranial direct current stimulation (tDCS) on working memory and learning serves as paradigm for translational research starting from animal models via experimental studies in humans to clinical applications in the field of behavioral training and psychotherapy. (3) High quality randomized controlled clinical trials (RCTs) which are mandatory for establishing therapeutic applications can be accompanied by basic research characterizing mechanisms of action. Two current randomized placebo-controlled trials (DepressionDC,clinicaltrials.gov: NCT02530164; Psychotherapy Plus,clinicaltrials.gov: NCT02633449) will be presented including a novel mode of controlled tDCS application; research questions from this trial for preclinical studies will be discussed. Conclusion In sum, the natural boundaries of translational research from bench to bed between cellular models/animal models, healthy subjects and patient populations need to be systematically addressed in order to speed up the process of TBS development towards treatment. These examples require forward and reverse translational research. The GCBS may serve as model for further coordinated programs following a recently established hub-and-spoke structure. Supported by the Federal Ministry of Research and Education (“Forschungsnetz fur psychische Erkrankungen”, German Center for Brain Stimulation – GCBS, FKZ: 01EE1403) .

Clinical anatomy leading the way for solutions: An important paradigm for translational research

Clinical anatomy leading the way for solutions: An important paradigm for translational research

Cohort Profile: African Collaborative Center for Microbiome and Genomics Research (ACCME)

Abstract 65 Background: Cervical cancer is the second most common cancer in Africa. Much remains unknown about the prevalence and pathogenicity of human papillomavirus (HPV) types and the mechanism of disease, and there is a need for new biomarkers for screening programs. Methods: ACCME is a multicenter prospective cohort study of host germline, somatic and HPV genomics and epigenomics, and vaginal microenvironment; and their association with cervical cancer in 10,000 HIV negative women in Nigeria. Data on demographic, lifestyle, medical history, serum, germline DNA, HPV genotype, and vaginal pH are collected at baseline and during follow up visits every 6 months. Samples of exfoliated cervical cells are analyzed for high risk HPV with Roche LINEAR ARRAY and vaginal bacterial composition and abundance are characterized by deep sequencing of barcoded 16S rRNA gene fragments (V4) on a Illumina MiSeq platform. Colposcopies and biopsies are conducted on participants with clinical lesions and those with persistent high risk HPV infections. Results: By December 2015, 10,000 participants had been enrolled in the ACCME cohort. The mean (SD) age of the study participants at baseline was 40 (10) years. Most of the participants were married (76%), attended university (44%), and had professional jobs (37%). All the study participants have had vaginal sex, 17% have had oral sex, and only 2% have ever had anal sex. We found 30% of the study participants were HPV positive and 70% were HPV negative. The mean (SD) vaginal pH in the study population was 5.2 (0.5). Further analyses to characterize high-risk HPV types and determine persistence will be conducted at each follow up visit. Also, characterization of cervical cytokines and vaginal microbiome will be conducted after the follow up visits for all participants have been conducted. Conclusions: ACCME is a paradigm for translational research in biomarker discovery that addresses high impact public health challenges affecting women's health in Africa and the rest of the world. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

Implementation Research: The Fourth Movement of the Unfinished Translation Research Symphony.

Highlights The translational research paradigm has had a dynamic history. We propose further evolution of the paradigm to recognize the complex iterative/recursive nature of the translational research process, the feedback loops and intersections that can occur between various steps in the process, as well as the nonlinear progression from fundamental discovery science to population health impact in real-world settings. Current evidence shows that the biomedical research enterprise has been highly successful in early translational research while much less success can be demonstrated for late phase translational research, especially T4 translation research. The stakes for T4 translation research and implementation science are very high because complete execution of all steps in the translational research spectrum is required for maximum population health impact. The welcome news is that there is an ongoing trans-NIH effort that is contributing to a growing symphony of activity within dissemination and implementation research.

The Cholinergic Anti-Inflammatory Pathway: A Novel Paradigm for Translational Research in Neuroimmunology

Inflammation is a complex biologic response to gross traumatic injury, endogenous ligands, or exogenous ligands. The inflammatory response is essential for reestablishing organismal homeostasis. It must be meticulously monitored and tightly regulated as over- or under activation of the inflammatory response can cause morbidity and even mortality. Emerging evidence has begun to depict the molecular mechanisms by which inflammation is regulated via the nervous system; that is, inflammation is controlled by neuroimmunologic circuitry operating in a reflexive continuum. Known as the inflammatory reflex arc, this pathway exhibits an afferent and efferent arc: both of which derive from vagal nerve fibers. The afferent arc is comprised of vagal receptors detecting specific ligands indicating injury. An activated afferent arc will initiate the efferent arc, the cholinergic anti-inflammatory pathway, which regulates immunologically-mediated inflammation. Recent research has demonstrated that this pathway can be modulated with vagus nerve stimulation, providing a potential therapeutic option for a variety of inflammatory conditions. Here, we review the neuroimmunological mechanisms of the inflammatory reflex arc. Furthermore, we analyze current research and discuss potential therapeutic implications of the cholinergic antiinflammatory pathway.

Knowledge translation in men's health research: development and delivery of content for use online.

BackgroundMen can be hard to reach with face-to-face health-related information, while increasingly, research shows that they are seeking health information from online sources. Recognizing this trend, there is merit in developing innovative online knowledge translation (KT) strategies capable of translating research on men’s health into engaging health promotion materials. While the concept of KT has become a new mantra for researchers wishing to bridge the gap between research evidence and improved health outcomes, little is written about the process, necessary skills, and best practices by which researchers can develop online knowledge translation.ObjectiveOur aim was to illustrate some of the processes and challenges involved in, and potential value of, developing research knowledge online to promote men’s health.MethodsWe present experiences of KT across two case studies of men’s health. First, we describe a study that uses interactive Web apps to translate knowledge relating to Canadian men’s depression. Through a range of mechanisms, study findings were repackaged with the explicit aim of raising awareness and reducing the stigma associated with men’s depression and/or help-seeking. Second, we describe an educational resource for teenage men about unintended pregnancy, developed for delivery in the formal Relationship and Sexuality Education school curricula of Ireland, Northern Ireland (United Kingdom), and South Australia. The intervention is based around a Web-based interactive film drama entitled “If I Were Jack”.ResultsFor each case study, we describe the KT process and strategies that aided development of credible and well-received online content focused on men’s health promotion. In both case studies, the original research generated the inspiration for the interactive online content and the core development strategy was working with a multidisciplinary team to develop this material through arts-based approaches. In both cases also, there is an acknowledgment of the need for gender and culturally sensitive information. Both aimed to engage men by disrupting stereotypes about men, while simultaneously addressing men through authentic voices and faces. Finally, in both case studies we draw attention to the need to think beyond placement of content online to delivery to target audiences from the outset.ConclusionsThe case studies highlight some of the new skills required by academics in the emerging paradigm of translational research and contribute to the nascent literature on KT. Our approach to online KT was to go beyond dissemination and diffusion to actively repackage research knowledge through arts-based approaches (videos and film scripts) as health promotion tools, with optimal appeal, to target male audiences. Our findings highlight the importance of developing a multidisciplinary team to inform the design of content, the importance of adaptation to context, both in terms of the national implementation context and consideration of gender-specific needs, and an integrated implementation and evaluation framework in all KT work.

Metabonomics and diagnostics.

Metabonomic techniques have considerable potential in the field of clinical diagnostics, typifying the application of a translational research paradigm. Care must be taken at all stages to apply appropriate methodology with accurate patient selection and profiling, and rigorous data acquisition and handling, to ensure clinical validity.An ever-increasing number of publications in a wide range of diseases and diverse patient groups suggest a variety of potential clinical uses; prospective studies in large validation cohorts are required to bring metabonomics into routine clinical practice. In this chapter, the utility of metabonomics as a diagnostic tool will be discussed.

Evolving toward a human-cell based and multiscale approach to drug discovery for CNS disorders.

A disruptive approach to therapeutic discovery and development is required in order to significantly improve the success rate of drug discovery for central nervous system (CNS) disorders. In this review, we first assess the key factors contributing to the frequent clinical failures for novel drugs. Second, we discuss cancer translational research paradigms that addressed key issues in drug discovery and development and have resulted in delivering drugs with significantly improved outcomes for patients. Finally, we discuss two emerging technologies that could improve the success rate of CNS therapies: human induced pluripotent stem cell (hiPSC)-based studies and multiscale biology models. Coincident with advances in cellular technologies that enable the generation of hiPSCs directly from patient blood or skin cells, together with methods to differentiate these hiPSC lines into specific neural cell types relevant to neurological disease, it is also now possible to combine data from large-scale forward genetics and post-mortem global epigenetic and expression studies in order to generate novel predictive models. The application of systems biology approaches to account for the multiscale nature of different data types, from genetic to molecular and cellular to clinical, can lead to new insights into human diseases that are emergent properties of biological networks, not the result of changes to single genes. Such studies have demonstrated the heterogeneity in etiological pathways and the need for studies on model systems that are patient-derived and thereby recapitulate neurological disease pathways with higher fidelity. In the context of two common and presumably representative neurological diseases, the neurodegenerative disease Alzheimer’s Disease, and the psychiatric disorder schizophrenia, we propose the need for, and exemplify the impact of, a multiscale biology approach that can integrate panomic, clinical, imaging, and literature data in order to construct predictive disease network models that can (i) elucidate subtypes of syndromic diseases, (ii) provide insights into disease networks and targets and (iii) facilitate a novel drug screening strategy using patient-derived hiPSCs to discover novel therapeutics for CNS disorders.