Valerie M Schaibley

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• Schaibley, V. M., Ramos, I. N., Woosley, R. L., Curry, S., Hays, S., & Ramos, K. S. (2022). Limited Genomics Training Among Physicians Remains a Barrier to Genomics-Based Implementation of Precision Medicine. Frontiers in medicine, 9, 757212.
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  The field of precision medicine has undergone significant growth over the past 10 years. Despite increasing applications of clinical genetic and genomic testing, studies consistently report limited knowledge of genetics and genomics among healthcare providers. This study explored barriers to the implementation of precision medicine by surveying physicians working in a large academic medical center. We assessed prior training in genetics, use of genetic testing in the clinic, desire for additional resources in genetics and genomic medicine and perceived barriers to successful integration of precision medicine. Only 20% of respondents reported moderate or extensive training in genetics. Physicians with limited or no training in genetics were less likely to have ordered a genetic test for any purpose. Furthermore, 41% of physicians responded that their lack of training identifying appropriate genetic tests and how to interpret genetic testing results was the most significant barrier to ordering genetic testing for their patients. These findings suggest that future efforts to realize the promise of precision medicine should focus on the integration of training programs for non-genetics trained healthcare providers.
• Schaibley, V. M., Woosley, R. L., Ramos, K. S., Hays, S., Curry, S., & Ramos, I. N. (2022). Limited Genomics Training Among Physicians Remains a Barrier to Genomics-Based Implementation of Precision Medicine. Frontiers in Medicine. doi:10.3389/fmed.2022.757212
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  The field of precision medicine has undergone significant growth over the past 10 years. Despite increasing applications of clinical genetic and genomic testing, studies consistently report limited knowledge of genetics and genomics among healthcare providers. This study explored barriers to the implementation of precision medicine by surveying physicians working in a large academic medical center. We assessed prior training in genetics, use of genetic testing in the clinic, desire for additional resources in genetics and genomic medicine and perceived barriers to successful integration of precision medicine. Only 20% of respondents reported moderate or extensive training in genetics. Physicians with limited or no training in genetics were less likely to have ordered a genetic test for any purpose. Furthermore, 41% of physicians responded that their lack of training identifying appropriate genetic tests and how to interpret genetic testing results was the most significant barrier to ordering genetic testing for their patients. These findings suggest that future efforts to realize the promise of precision medicine should focus on the integration of training programs for non-genetics trained healthcare providers.
• Schaibley, V. M., Quinn, D., Stallman, C., & Kieran, S. (2021). Rethinking genetic counseling clinical skills training in the time of COVID‐19. Journal of Genetic Counseling, 30(5), 1310-1315. doi:10.1002/jgc4.1503
• Silva, P. J., Schaibley, V. M., & Ramos, K. S. (2018). Academic medical centers as innovation ecosystems to address population -omics challenges in precision medicine. Journal of translational medicine, 16(1), 28.
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  While the promise of the Human Genome Project provided significant insights into the structure of the human genome, the complexities of disease at the individual level have made it difficult to utilize -omic information in clinical decision making. Some of the existing constraints have been minimized by technological advancements that have reduced the cost of sequencing to a rate far in excess of Moore's Law (a halving in cost per unit output every 18 months). The reduction in sequencing costs has made it economically feasible to create large data commons capturing the diversity of disease across populations. Until recently, these data have primarily been consumed in clinical research, but now increasingly being considered in clinical decision- making. Such advances are disrupting common diagnostic business models around which academic medical centers (AMCs) and molecular diagnostic companies have collaborated over the last decade. Proprietary biomarkers and patents on proprietary diagnostic content are no longer driving biomarker collaborations between industry and AMCs. Increasingly the scope of the data commons and biorepositories that AMCs can assemble through a nexus of academic and pharma collaborations is driving a virtuous cycle of precision medicine capabilities that make an AMC relevant and highly competitive. A rebalancing of proprietary strategies and open innovation strategies is warranted to enable institutional precision medicine asset portfolios. The scope of the AMC's clinical trial and research collaboration portfolios with industry are increasingly dependent on the currency of data, and less on patents. Intrapeneurial support of internal service offerings, clinical trials and clinical laboratory services for example, will be important new points of emphasis at the academic-industry interface. Streamlining these new models of industry collaboration for AMCs are a new area for technology transfer offices to offer partnerships and to add value beyond the traditional intellectual property offering.
• Schaibley, V. M., Zawistowski, M., Wegmann, D., Ehm, M. G., Nelson, M. R., St Jean, P. L., Abecasis, G. R., Novembre, J., Zöllner, S., & Li, J. Z. (2013). The influence of genomic context on mutation patterns in the human genome inferred from rare variants. Genome research, 23(12), 1974-84.
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  Understanding patterns of spontaneous mutations is of fundamental interest in studies of human genome evolution and genetic disease. Here, we used extremely rare variants in humans to model the molecular spectrum of single-nucleotide mutations. Compared to common variants in humans and human-chimpanzee fixed differences (substitutions), rare variants, on average, arose more recently in the human lineage and are less affected by the potentially confounding effects of natural selection, population demographic history, and biased gene conversion. We analyzed variants obtained from a population-based sequencing study of 202 genes in >14,000 individuals. We observed considerable variability in the per-gene mutation rate, which was correlated with local GC content, but not recombination rate. Using >20,000 variants with a derived allele frequency ≤ 10(-4), we examined the effect of local GC content and recombination rate on individual variant subtypes and performed comparisons with common variants and substitutions. The influence of local GC content on rare variants differed from that on common variants or substitutions, and the differences varied by variant subtype. Furthermore, recombination rate and recombination hotspots have little effect on rare variants of any subtype, yet both have a relatively strong impact on multiple variant subtypes in common variants and substitutions. This observation is consistent with the effect of biased gene conversion or selection-dependent processes. Our results highlight the distinct biases inherent in the initial mutation patterns and subsequent evolutionary processes that affect segregating variants.
• Bedoyan, J. K., Schaibley, V. M., Peng, W., Bai, Y., Mondal, K., Shetty, A. C., Durham, M., Micucci, J. A., Dhiraaj, A., Skidmore, J. M., Kaplan, J. B., Skinner, C., Schwartz, C. E., Antonellis, A., Zwick, M. E., Cavalcoli, J. D., Li, J. Z., & Martin, D. M. (2012). Disruption of RAB40AL function leads to Martin--Probst syndrome, a rare X-linked multisystem neurodevelopmental human disorder. Journal of medical genetics, 49(5), 332-40.
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  Martin--Probst syndrome (MPS) is a rare X-linked disorder characterised by deafness, cognitive impairment, short stature and distinct craniofacial dysmorphisms, among other features. The authors sought to identify the causative mutation for MPS.
• Arlt, M. F., Mulle, J. G., Schaibley, V. M., Ragland, R. L., Durkin, S. G., Warren, S. T., & Glover, T. W. (2009). Replication stress induces genome-wide copy number changes in human cells that resemble polymorphic and pathogenic variants. American journal of human genetics, 84(3), 339-50.
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  Copy number variants (CNVs) are an important component of genomic variation in humans and other mammals. Similar de novo deletions and duplications, or copy number changes (CNCs), are now known to be a major cause of genetic and developmental disorders and to arise somatically in many cancers. A major mechanism leading to both CNVs and disease-associated CNCs is meiotic unequal crossing over, or nonallelic homologous recombination (NAHR), mediated by flanking repeated sequences or segmental duplications. Others appear to involve nonhomologous end joining (NHEJ) or aberrant replication suggesting a mitotic cell origin. Here we show that aphidicolin-induced replication stress in normal human cells leads to a high frequency of CNCs of tens to thousands of kilobases across the human genome that closely resemble CNVs and disease-associated CNCs. Most deletion and duplication breakpoint junctions were characterized by short (
• Arlt, M. F., Mullé, J. G., Schaibley, V. M., Ragland, R. L., Durkin, S. G., Warren, S. T., & Glover, T. W. (2009).

  Replication Stress Induces Genome-wide Copy Number Changes in Human Cells that Resemble Polymorphic and Pathogenic Variants

  . American Journal of Human Genetics. doi:10.1016/j.ajhg.2009.01.024
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  Copy number variants (CNVs) are an important component of genomic variation in humans and other mammals. Similar de novo deletions and duplications, or copy number changes (CNCs), are now known to be a major cause of genetic and developmental disorders and to arise somatically in many cancers. A major mechanism leading to both CNVs and disease-associated CNCs is meiotic unequal crossing over, or nonallelic homologous recombination (NAHR), mediated by flanking repeated sequences or segmental duplications. Others appear to involve nonhomologous end joining (NHEJ) or aberrant replication suggesting a mitotic cell origin. Here we show that aphidicolin-induced replication stress in normal human cells leads to a high frequency of CNCs of tens to thousands of kilobases across the human genome that closely resemble CNVs and disease-associated CNCs. Most deletion and duplication breakpoint junctions were characterized by short (