Browsing by Subject "Phenotyping"

Now showing 1 - 8 of 8
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    Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease
    (Elsevier, 2022) Hemnes, Anna R.; Leopold, Jane A.; Radeva, Milena K.; Beck, Gerald J.; Abidov, Aiden; Aldred, Micheala A.; Barnard, John; Rosenzweig, Erika B.; Borlaug, Barry A.; Chung, Wendy K.; Comhair, Suzy A. A.; Desai, Ankit A.; Dubrock, Hilary M.; Erzurum, Serpil C.; Finet, J. Emanuel; Frantz, Robert P.; Garcia, Joe G. N.; Geraci, Mark W.; Gray, Michael P.; Grunig, Gabriele; Hassoun, Paul M.; Highland, Kristin B.; Hill, Nicholas S.; Hu, Bo; Kwon, Deborah H.; Jacob, Miriam S.; Jellis, Christine L.; Larive, A. Brett; Lempel, Jason K.; Maron, Bradley A.; Mathai, Stephen C.; McCarthy, Kevin; Mehra, Reena; Nawabit, Rawan; Newman, John H.; Olman, Mitchell A.; Park, Margaret M.; Ramos, Jose A.; Renapurkar, Rahul D.; Rischard, Franz P.; Sherer, Susan G.; Tang, W. H. Wilson; Thomas, James D.; Vanderpool, Rebecca R.; Waxman, Aaron B.; Wilcox, Jennifer D.; Yuan, Jason X-J; Horn, Evelyn M.; PVDOMICS Study Group; Medicine, School of Medicine
    Background: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. Objectives: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. Methods: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. Results: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. Conclusions: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification.
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    Comprehensive Evaluation of the 5XFAD Mouse Model for Preclinical Testing Applications: A MODEL-AD Study
    (Frontiers Media, 2021-07-23) Oblak, Adrian L.; Lin, Peter B.; Kotredes, Kevin P.; Pandey, Ravi S.; Garceau, Dylan; Williams, Harriet M.; Uyar, Asli; O’Rourke, Rita; O’Rourke, Sarah; Ingraham, Cynthia; Bednarczyk, Daria; Belanger, Melisa; Cope, Zackary A.; Little, Gabriela J.; Williams, Sean-Paul G.; Ash, Carl; Bleckert, Adam; Ragan, Tim; Logsdon, Benjamin A.; Mangravite, Lara M.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Carter, Gregory W.; Howell, Gareth R.; Sasner, Michael; Lamb, Bruce T.; Radiology and Imaging Sciences, School of Medicine
    The ability to investigate therapeutic interventions in animal models of neurodegenerative diseases depends on extensive characterization of the model(s) being used. There are numerous models that have been generated to study Alzheimer’s disease (AD) and the underlying pathogenesis of the disease. While transgenic models have been instrumental in understanding AD mechanisms and risk factors, they are limited in the degree of characteristics displayed in comparison with AD in humans, and the full spectrum of AD effects has yet to be recapitulated in a single mouse model. The Model Organism Development and Evaluation for Late-Onset Alzheimer’s Disease (MODEL-AD) consortium was assembled by the National Institute on Aging (NIA) to develop more robust animal models of AD with increased relevance to human disease, standardize the characterization of AD mouse models, improve preclinical testing in animals, and establish clinically relevant AD biomarkers, among other aims toward enhancing the translational value of AD models in clinical drug design and treatment development. Here we have conducted a detailed characterization of the 5XFAD mouse, including transcriptomics, electroencephalogram, in vivo imaging, biochemical characterization, and behavioral assessments. The data from this study is publicly available through the AD Knowledge Portal.
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    The Current Landscape of Genetic Testing in Cardiovascular Malformations: Opportunities and Challenges
    (Frontiers, 2016-07-25) Landis, Benjamin J.; Ware, Stephanie M.; Department of Pediatrics, IU School of Medicine
    Human cardiovascular malformations (CVMs) frequently have a genetic contribution. Through the application of novel technologies, such as next-generation sequencing, DNA sequence variants associated with CVMs are being identified at a rapid pace. While clinicians are now able to offer testing with NGS gene panels or whole exome sequencing to any patient with a CVM, the interpretation of genetic variation remains problematic. Variable phenotypic expression, reduced penetrance, inconsistent phenotyping methods, and the lack of high-throughput functional testing of variants contribute to these challenges. This article elaborates critical issues that impact the decision to broadly implement clinical molecular genetic testing in CVMs. Major benefits of testing include establishing a genetic diagnosis, facilitating cost-effective screening of family members who may have subclinical disease, predicting recurrence risk in offsprings, enabling early diagnosis and anticipatory management of CV and non-CV disease phenotypes, predicting long-term outcomes, and facilitating the development of novel therapies aimed at disease improvement or prevention. Limitations include financial cost, psychosocial cost, and ambiguity of interpretation of results. Multiplex families and patients with syndromic features are two groups where disease causation could potentially be firmly established. However, these account for the minority of the overall CVM population, and there is increasing recognition that genotypes previously associated with syndromes also exist in patients who lack non-CV findings. In all circumstances, ongoing dialog between cardiologists and clinical geneticists will be needed to accurately interpret genetic testing and improve these patients' health. This may be most effectively implemented by the creation and support of CV genetics services at centers committed to pursuing testing for patients.
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    Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morp
    (Annual Reviews, 2022) Naqvi, Sahin; Hoskens, Hanne; Wilke, Franziska; Weinberg, Seth M.; Shaffer, John R.; Walsh, Susan; Shriver, Mark D.; Wysocka, Joanna; Claes, Peter; Biology, School of Science
    Variations in the form of the human face, which plays a role in our individual identities and societal interactions, have fascinated scientists and artists alike. Here, we review our current understanding of the genetics underlying variation in craniofacial morphology and disease-associated dysmorphology, synthesizing decades of progress on Mendelian syndromes in addition to more recent results from genome-wide association studies of human facial shape and disease risk. We also discuss the various approaches used to phenotype and quantify facial shape, which are of particular importance due to the complex, multipartite nature of the craniofacial form. We close by discussing how experimental studies have contributed and will further contribute to our understanding of human genetic variation and then proposing future directions and applications for the field.
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    Enhancing Our Genetic Knowledge of Human Iris Pigmentation and Facial Morphology
    (2019-12) Eller, Ryan; Walsh, Susan; Berbari, Nicolas; Lapish, Christopher; Picard, Christine; Roper, Randall
    The biological underpinnings that control iris pigmentation and facial morphology are two areas of research that over the last decade are becoming more thoroughly investigated due to the increased affordability of genotyping and advances in technology allowing for more advanced analysis techniques. Despite the ease of access to the data and the tools required to perform iris pigmentation and facial morphological studies, there are still numerous challenges researchers must overcome when exploring the genetics of these complex phenotypes. Some of these challenges include difficulty in working with the bioinformatic programs designed to analyze genetic associations, the inability to define a phenotype that captures the true nature of these traits, and analysis techniques that fail to model complex gene-gene interactions and their effect on a phenotype or phenotypes of interest. In this body of work, I attempted to address these challenges by designing a bioinformatic pipeline, Odyssey, that bridges the communication gaps between various data preparation programs and the programs that analyze genomic data. With this program, genome-wide association studies (GWAS) could be conducted in a quicker, more efficient, and easier manner. I also redefined iris color as a quantitative measurement of pre-defined color classes. In this way it is possible to define and quantify the unique and intricate mixtures of color, which allows for the identification of known and novel variants that affect individual iris color. I also improved upon current prediction models by developing a neural network model capable of predicting a quantitative output to four pre-defined classes; blue/grey, light brown (hazel), perceived green, and dark brown. I examined the effects of defining a simple facial morphology phenotype that more accurately captures the lower face and jaw shape. I then analyzed this phenotype via a GWAS and found several novel variants that may be associated with a square and diamond shaped face. Lastly, I demonstrated that structural equation modeling can be used in combination with traditional GWAS to examine interactions amongst associated variants, which unearths potential biological relationships that impact the multifaceted phenotype of facial morphology.
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    In Vitro, In Vivo, and In Silico Methods for Assessment of Muscle Size and Muscle Growth Regulation
    (Wolters Kluwer, 2020-04-14) Rupert, Joseph E.; Jengelley, Daenique H. A.; Zimmers, Teresa A.; Biochemistry and Molecular Biology, School of Medicine
    Trauma, burn injury, sepsis, and ischemia lead to acute and chronic loss of skeletal muscle mass and function. Healthy muscle is essential for eating, posture, respiration, reproduction, and mobility, as well as for appropriate function of the senses including taste, vision, and hearing. Beyond providing support and contraction, skeletal muscle also exerts essential roles in temperature regulation, metabolism, and overall health. As the primary reservoir for amino acids, skeletal muscle regulates whole-body protein and glucose metabolism by providing substrate for protein synthesis and supporting hepatic gluconeogenesis during illness and starvation. Overall, greater muscle mass is linked to greater insulin sensitivity and glucose disposal, strength, power, and longevity. In contrast, low muscle mass correlates with dysmetabolism, dysmobility, and poor survival. Muscle mass is highly plastic, appropriate to its role as reservoir, and subject to striking genetic control. Defining mechanisms of muscle growth regulation holds significant promise to find interventions that promote health and diminish morbidity and mortality after trauma, sepsis, inflammation, and other systemic insults. In this invited review, we summarize techniques and methods to assess and manipulate muscle size and muscle mass in experimental systems, including cell culture and rodent models. These approaches have utility for studies of myopenia, sarcopenia, cachexia, and acute muscle growth or atrophy in the setting of health or injury.
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    Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions
    (Springer Nature, 2024-04-15) Neuhaus, Emily; Rea, Hannah; Jones, Elizabeth; Benavidez, Hannah; Miles, Conor; Whiting, Alana; Johansson, Margaret; Eayrs, Curtis; Kurtz‑Nelson, Evangeline C.; Earl, Rachel; Bernier, Raphael A.; Eichler, Evan E.; Pediatrics, School of Medicine
    Background: Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD - ADNP, CHD8, and DYRK1A - with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes. Methods: Phenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features. Results: Patterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group. Conclusions: Despite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.
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    Tangent functional connectomes uncover more unique phenotypic traits
    (Elsevier, 2023-08-12) Abbas, Kausar; Liu, Mintao; Wang, Michael; Duong-Tran, Duy; Tipnis, Uttara; Amico, Enrico; Kaplan, Alan D.; Dzemidzic, Mario; Kareken, David; Ances, Beau M.; Harezlak, Jaroslaw; Goñi, Joaquín; Neurology, School of Medicine
    Functional connectomes (FCs) containing pairwise estimations of functional couplings between pairs of brain regions are commonly represented by correlation matrices. As symmetric positive definite matrices, FCs can be transformed via tangent space projections, resulting into tangent-FCs. Tangent-FCs have led to more accurate models predicting brain conditions or aging. Motivated by the fact that tangent-FCs seem to be better biomarkers than FCs, we hypothesized that tangent-FCs have also a higher fingerprint. We explored the effects of six factors: fMRI condition, scan length, parcellation granularity, reference matrix, main-diagonal regularization, and distance metric. Our results showed that identification rates are systematically higher when using tangent-FCs across the “fingerprint gradient” (here including test-retest, monozygotic and dizygotic twins). Highest identification rates were achieved when minimally (0.01) regularizing FCs while performing tangent space projection using Riemann reference matrix and using correlation distance to compare the resulting tangent-FCs. Such configuration was validated in a second dataset (resting-state).