Read and assembly metrics inconsequential for clinical utility of whole-genome sequencing in mapping outbreaks

ABSTRACTBACKGROUNDGenetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.METHODSRetrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.FINDINGSThe diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.DISCUSSIONThese findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

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Clinical utility of whole-genome sequencing in a large ALS cohort

Journal of the Neurological Sciences ◽

10.1016/j.jns.2021.117740 ◽

2021 ◽

Vol 429 ◽

pp. 117740

Author(s):

Maurizio Grassano ◽

Andrea Calvo ◽

Cristina Moglia ◽

Antonio Canosa ◽

Rosario Vasta ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Whole Genome

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Clinical utility of whole genome sequencing in hematological neoplasms.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.7028 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 7028-7028

Author(s):

Jesus Gutierrez-Abril ◽

Daniel Leongamornlert ◽

Yangyu Zhou ◽

SooWah Lee ◽

Max Levine ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Lymphoblastic Leukemia ◽

False Negative ◽

Control Sample ◽

Leukemic Cells ◽

Training Dataset ◽

Whole Genome ◽

Hematological Neoplasms

7028 Background: Hematological neoplasms are often characterized by acute onset and rapid disease progression. Cytogenetics, FISH, SNP arrays, targeted DNA and RNA sequencing are performed to inform diagnosis, risk stratification and guide treatment decisions. Whole genome sequencing (WGS) offers the opportunity to comprehensively characterize all putative biomarkers in a single assay. However, a limitation in current WGS implementation is the requirement for a germline sample, as sources of control tissue are frequently contaminated with leukemic cells resulting in false negative calls. Methods: To evaluate the clinical utility and feasibility of WGS in the diagnostic work up of leukemias, we analyzed 57 B-cell acute lymphoblastic leukemia (B-ALL) from the UKALL14 trial (NCT01085617) with no informative biomarkers at diagnosis. WGS analysis was performed on the leukemic sample and a matching control sample (with minimal residual disease level of <1%). Using this dataset, we trained the development of an unmatched (uWGS) analytical workflow (Isabl) for a tumor only WGS study. This workflow was validated across 20 hematologic neoplasms (12 B-ALL, 6 AML and 2 T-ALL). Results: Among the 57 cases, 5 failed QC owing to low tumor content (<25%). Of the remaining 52, putative biomarkers of clinical relevance were identified by WGS in 69% (36/52). These included delineation of aberrant karyotypes where conventional chromosome banding failed (4/52), the detection of newly described fusion genes (such as IGH-DUX4 and EP300-ZNF384 in 21/52) and recurrent gene mutations (i.e. PAX5 P80R, ZEB2 H1038R in 11/52). uWGS workflow in our training dataset captured 86% of biomarkers identified in the matched analysis (3/3 ploidy, 21/22 fusion and 7/11 coding). Concordance between the matched and uWGS workflow for arm-level and focal copy number alterations (CNAs), structural variants (SVs) and annotated hotspot mutations were 94%, 84%, 83% and 100% respectively. Independent validation of the uWGS workflow across 20 myeloid and lymphoid neoplasms, recapitulated all clinically reported biomarkers (14/15 CNAs, 16/16 SVs) as well as captured two novel findings not previously detected in two B-ALL patients, to include a focal deletion in BTG1 and the fusion gene P2RY8-CRLF2, as well as a NOTCH1 translocation in T-ALL. Conclusions: Our findings demonstrate that comprehensive WGS allows for the detection of the same biomarkers as a range of clinical assays using a single test, as well as the opportunity to discover novel clinical and research findings to support future correlative research and biomarker development. Additionally, we developed and validated an uWGS workflow that allows WGS analysis of hematopoietic neoplasms at diagnosis, enabling detection and reporting of clinically relevant biomarkers.

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Clinical utility of whole genome sequencing for the detection of mitochondrial genome mutations

Journal of Genetics and Genomics ◽

10.1016/j.jgg.2020.03.001 ◽

2020 ◽

Vol 47 (3) ◽

pp. 167-169

Author(s):

Ammar Husami ◽

Jesse Slone ◽

Jenice Brown ◽

Meghan Bromwell ◽

C. Alexander Valencia ◽

...

Keyword(s):

Mitochondrial Genome ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Whole Genome

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Rapid Whole Genome Sequencing Has Clinical Utility in Children in the PICU*

Pediatric Critical Care Medicine ◽

10.1097/pcc.0000000000002056 ◽

2019 ◽

Vol 20 (11) ◽

pp. 1007-1020 ◽

Cited By ~ 15

Author(s):

Erica F. Sanford ◽

Michelle M. Clark ◽

Lauge Farnaes ◽

Matthew R. Williams ◽

James C. Perry ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Whole Genome

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A meta-analysis of the diagnostic sensitivity and clinical utility of genome sequencing, exome sequencing and chromosomal microarray in children with suspected genetic diseases

10.1101/255299 ◽

2018 ◽

Author(s):

Michelle M. Clark ◽

Zornitza Stark ◽

Lauge Farnaes ◽

Tiong Y. Tan ◽

Susan M. White ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Meta Analysis ◽

Genetic Diseases ◽

Diagnostic Sensitivity ◽

Whole Genome ◽

Significant Difference ◽

Chromosomal Microarrays

AbstractIMPORTANCEGenetic diseases are a leading cause of childhood mortality. Whole genome sequencing (WGS) and whole exome sequencing (WES) are relatively new methods for diagnosing genetic diseases.OBJECTIVESCompare the diagnostic sensitivity (rate of causative, pathogenic or likely pathogenic genotypes in known disease genes) and rate of clinical utility (proportion in whom medical or surgical management was changed by diagnosis) of WGS, WES, and chromosomal microarrays (CMA) in children with suspected genetic diseases.DATA SOURCES AND STUDY SELECTIONSystematic review of the literature (January 2011 - August 2017) for studies of diagnostic sensitivity and/or clinical utility of WGS, WES, and/or CMA in children with suspected genetic diseases. 2% of identified studies met selection criteria.DATA EXTRACTION AND SYNTHESISTwo investigators extracted data independently following MOOSE/PRISMA guidelines.MAIN OUTCOMES AND MEASURESPooled rates and 95% Cl were estimated with a random-effects model. Metaanalysis of the rate of diagnosis was based on test type, family structure, and site of testing.RESULTSIn 36 observational series and one randomized control trial, comprising 20,068 children, the diagnostic sensitivity of WGS (0.41, 95% Cl 0.34-0.48, I2=44%) and WES (0.35, 95% Cl 0.31-0.39, I2=85%) were qualitatively greater than CMA (0.10, 95% Cl 0.08-0.12, I2=81%). Subgroup meta-analyses showed that the diagnostic sensitivity of WGS was significantly greater than CMA in studies published in 2017 (P<.0001, I2=13% and I2=40%, respectively), and the diagnostic sensitivity of WES was significantly greater than CMA in studies featuring within-cohort comparisons (P<001, I2=36%). Evidence for a significant difference in the diagnostic sensitivity of WGS and WES was lacking. In studies featuring within-cohort comparisons of singleton and trio WGS/WES, the likelihood of diagnosis was significantly greater for trios (odds ratio 2.04, 95% Cl 1.62-2.56, I2=12%; P<.0001). The diagnostic sensitivity of WGS/WES with hospital-based interpretation (0.41, 95% Cl 0.38-0.45, I2=50%) was qualitatively higher than that of reference laboratories (0.28, 95% Cl 0.24-0.32, I2=81%); this difference was significant in meta-analysis of studies published in 2017 (P=.004, I2=34% and I2=26%, respectively). The rates of clinical utility of WGS (0.27, 95% Cl 0.17-0.40, I2=54%) and WES (0.18, 95% Cl 0.13-0.24, I2-77%) were higher than CMA (0.06, 95% Cl 0.05-0.07, I2=42%); this difference was significant in meta-analysis of WGS vs CMA (P<.0001).CONCLUSIONS AND RELEVANCEIn children with suspected genetic diseases, the diagnostic sensitivity and rate of clinical utility of WGS/WES were greater than CMA. Subgroups with higher WGS/WES diagnostic sensitivity were trios and those receiving hospital-based interpretation. WGS/WES should be considered a first-line genomic test for children with suspected genetic diseases.Key PointsQuestionWhat is the relative diagnostic sensitivity and clinical utility of different genome tests in children with suspected genetic diseases?FindingsWhole genome sequencing had greater diagnostic sensitivity and clinical utility than chromosomal microarrays. Testing parent-child trios had greater diagnostic sensitivity than proband singletons. Hospital-based testing had greater diagnostic sensitivity than reference laboratories.MeaningTrio genomic sequencing is the most sensitive diagnostic test for children with suspected genetic diseases.

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