Challenges of Identifying Clinically Actionable Genetic Variants for Precision Medicine

Carter, Tonia C.; He, Max M.

doi:10.1155/2016/3617572

Cited by 33 publications

(22 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Big data in healthcare is defined as “high-volume, high-velocity and/or high-variety information assets that demand cost-effective, innovative forms of information-processing that enable enhanced insight, decision making and process automation [ 2 , 3 ].” Many healthcare organizations already collect this “big data” in order to remain compliant with regulatory agencies, drive better business practice, maintain high standards for patient care, and perform efficient and effective record keeping [ 4 ]. Data is captured from many sources at a real time rapid pace known as velocity.…”

Section: Introductionmentioning

confidence: 99%

Leveraging healthcare utilization to explore outcomes from musculoskeletal disorders: methodology for defining relevant variables from a health services data repository

Rhon

Clewley

Young

et al. 2018

BMC Med Inform Decis Mak

View full text Add to dashboard Cite

BackgroundLarge healthcare databases, with their ability to collect many variables from daily medical practice, greatly enable health services research. These longitudinal databases provide large cohorts and longitudinal time frames, allowing for highly pragmatic assessment of healthcare delivery. The purpose of this paper is to discuss the methodology related to the use of the United States Military Health System Data Repository (MDR) for longitudinal assessment of musculoskeletal clinical outcomes, as well as address challenges of using this data for outcomes research.MethodsThe Military Health System manages care for approximately 10 million beneficiaries worldwide. Multiple data sources pour into the MDR from multiple levels of care (inpatient, outpatient, military or civilian facility, combat theater, etc.) at the individual patient level. To provide meaningful and descriptive coding for longitudinal analysis, specific coding for timing and type of care, procedures, medications, and provider type must be performed. Assumptions often made in clinical trials do not apply to these cohorts, requiring additional steps in data preparation to reduce risk of bias. The MDR has a robust system in place to validate the quality and accuracy of its data, reducing risk of analytic error. Details for making this data suitable for analysis of longitudinal orthopaedic outcomes are provided.ResultsAlthough some limitations exist, proper preparation and understanding of the data can limit bias, and allow for robust and meaningful analyses. There is the potential for strong precision, as well as the ability to collect a wide range of variables in very large groups of patients otherwise not captured in traditional clinical trials. This approach contributes to the improved understanding of the accessibility, quality, and cost of care for those with orthopaedic conditions.ConclusionThe MDR provides a robust pool of longitudinal healthcare data at the person-level. The benefits of using the MDR database appear to outweigh the limitations.

show abstract

Section: Introductionmentioning

confidence: 99%

Leveraging healthcare utilization to explore outcomes from musculoskeletal disorders: methodology for defining relevant variables from a health services data repository

Rhon

Clewley

Young

et al. 2018

BMC Med Inform Decis Mak

View full text Add to dashboard Cite

show abstract

“…Analysis was guided by the Standards and Guidelines from the American College of Medical Genetics for interpretation of sequence variants [38][39][40] . Clinically actionable variants were defined as those that could be justified in requesting for screening by an accredited medical ethics committee 41,42 . Each parental and embryo binary alignment map (BAM) and raw variant call format files were imported into VarSeq (GoldenHelix, USA).…”

Section: Methodsmentioning

confidence: 99%

Genome sequencing of human in vitro fertilisation embryos for pathogenic variation screening

Murphy

Samarasekera

Macaskill

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Whole-genome sequencing of preimplantation human embryos to detect and screen for genetic diseases is a technically challenging extension to preconception screening. combining preconception genetic screening with preimplantation testing of human embryos facilitates the detection of de novo mutations and self-validates transmitted variant detection in both the reproductive couple and the embryo's samples. Here we describe a trio testing workflow that involves whole-genome sequencing of amplified DNA from biopsied embryo trophectoderm cells and genomic DNA from both parents. Variant prediction software and annotation databases were used to assess variants of unknown significance and previously not described de novo variants in five single-gene preimplantation genetic testing couples and eleven of their embryos. Pathogenic variation, tandem repeat, copy number and structural variations were examined against variant calls for compound heterozygosity and predicted disease status was ascertained. Multiple trio testing showed complete concordance with known variants ascertained by single-nucleotide polymorphism array and uncovered de novo and transmitted pathogenic variants. this pilot study describes a method of whole-genome sequencing and analysis for embryo selection in high-risk couples to prevent early life fatal genetic conditions that adversely affect the quality of life of the individual and families. Whole-genome sequencing in the iVf clinic. For over two decades, preimplantation genetic testing (PGT) has been available for couples who are aware they carry a genetic condition or have had a child affected by a genetic disease. In vitro fertilisation (IVF) used in conjunction with monogenic PGT is available for couples to prevent transmission of known hereditary monogenic disorders. PGT for aneuploidy screens embryos for large segmental or whole-chromosome copy number changes and is commonly used for older women (>35 years) who have a history of infertility, miscarriages or chromosomally abnormal conceptions 1-3. The most recent developments in clinical PGT are low-coverage next-generation sequencing and Karyomapping, which uses a highly polymorphic single-nucleotide polymorphism (SNP) microarray to identify disease-causing haplotypes. Nextgeneration sequencing PGT for aneuploidy (typically <0.1× depth) is useful for high-throughput screening at a reasonable cost for detecting chromosomal aneuploidies, structural variations and large copy-number variations (CNVs) 4-6. In addition to pedigree analysis for monogenic disorders, Karyomapping has been reported to identify partial chromosomal aneuploidies as small as 1.8 Mb 7. For couples seeking to ascertain their risk of having an affected child, around 6,000 diseases exist that may be genetically screened for 8. A mutation or disease-causing variant in one or both copies of approximately 5,000 human genes can cause a syndromic disease or phenotype 9-14. Between 0.5-5% of infants are born with a genetic condition or disorder 15,16. The preconception genetic screening...

show abstract

“…Sequencing a single human genome generates about 200 gigabytes of data. Therefore, enormous challenges for analyzing large-scale NGS and clinical data still exist including data storage, processing, scaling, quality control management, and interpretation [22]. It is critical to develop an efficient computational framework and tools to analyze large-scale sequencing and clinical data.…”

Section: Methodsmentioning

confidence: 99%

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records

Zhao

McPherson

et al. 2016

PLoS ONE

Self Cite

View full text Add to dashboard Cite

BackgroundIt is unclear whether and how whole-genome sequencing (WGS) data can be used to implement genomic medicine. Our objective is to retrospectively evaluate whether WGS can facilitate improving prevention and care for patients with susceptibility to cancer syndromes.Methods and FindingsWe analyzed genetic mutations in 60 autosomal dominant cancer-predisposition genes in 300 deceased patients with WGS data and nearly complete long-term (over 30 years) medical records. To infer biological insights from massive amounts of WGS data and comprehensive clinical data in a short period of time, we developed an in-house analysis pipeline within the SeqHBase software framework to quickly identify pathogenic or likely pathogenic variants. The clinical data of the patients who carried pathogenic and/or likely pathogenic variants were further reviewed to assess their clinical conditions using their lifetime EHRs. Among the 300 participants, 5 (1.7%) carried pathogenic or likely pathogenic variants in 5 cancer-predisposing genes: one in APC, BRCA1, BRCA2, NF1, and TP53 each. When assessing the clinical data, each of the 5 patients had one or more different types of cancers, fully consistent with their genetic profiles. Among these 5 patients, 2 died due to cancer while the others had multiple disorders later in their lifetimes; however, they may have benefited from early diagnosis and treatment for healthier lives, had the patients had genetic testing in their earlier lifetimes.ConclusionsWe demonstrated a case study where the discovery of pathogenic or likely pathogenic germline mutations from population-wide WGS correlates with clinical outcome. The use of WGS may have clinical impacts to improve healthcare delivery.

show abstract

Challenges of Identifying Clinically Actionable Genetic Variants for Precision Medicine

Cited by 33 publications

References 98 publications

Leveraging healthcare utilization to explore outcomes from musculoskeletal disorders: methodology for defining relevant variables from a health services data repository

Leveraging healthcare utilization to explore outcomes from musculoskeletal disorders: methodology for defining relevant variables from a health services data repository

Genome sequencing of human in vitro fertilisation embryos for pathogenic variation screening

Pathogenic Mutations in Cancer-Predisposing Genes: A Survey of 300 Patients with Whole-Genome Sequencing and Lifetime Electronic Health Records

Contact Info

Product

Resources

About