Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even ...greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (
= 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (
= 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (
= 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
Current standards in clinical genetics recognize the need to establish the validity of gene-disease relationships as a first step in the interpretation of sequence variants. We describe our ...experience incorporating the ClinGen Gene-Disease Clinical Validity framework in our interpretation and reporting workflow for a clinical genome sequencing (cGS) test for individuals with rare and undiagnosed genetic diseases. This “reactive” gene curation is completed upon identification of candidate variants during active case analysis and within the test turn-around time by focusing on the most impactful evidence and taking advantage of the broad applicability of the framework to cover a wide range of disease areas. We demonstrate that reactive gene curation can be successfully implemented in support of cGS in a clinical laboratory environment, enabling robust clinical decision making and allowing all variants to be fully and appropriately considered and their clinical significance confidently interpreted.
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•Evaluation of gene-disease relationships is essential for variant interpretation•Experience using reactive gene curation to support a clinical genome test•Rigorous reactive gene curation enables robust clinical decision making
Clause et al. describe a clinical laboratory’s experience implementing reactive evaluation of gene-disease relationships within the interpretation and reporting workflow of a clinical genome sequencing test for rare genetic diseases. This work demonstrates that rigorous, reactive gene curation aids in variant interpretation and meets a critical need for clinical reporting.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
IMPORTANCE: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical ...management. OBJECTIVE: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. DESIGN, SETTING, AND PARTICIPANTS: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children’s hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. INTERVENTIONS: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. MAIN OUTCOMES AND MEASURES: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. RESULTS: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 21.1%; 95% CI, 15.1%-28.2% vs 17 of 165 10.3%; 95% CI, 6.1%-16.0%; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 31.0%; 95% CI, 24.5%-38.7% vs 27 of 178 15.0%; 95% CI, 10.2%-21.3%; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 28.0%; 95% CI, 21.2%-35.6%) and diagnostic efficacy (to 56 of 178 31.0%; 95% CI, 24.7%-38.8%). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT03290469
The use of whole‐genome sequencing (WGS) has accelerated the pace of gene discovery and highlighted the need for open and collaborative data sharing in the search for novel disease genes and ...variants. GeneMatcher (GM) is designed to facilitate connections between researchers, clinicians, health‐care providers, and others to help in the identification of additional patients with variants in the same candidate disease genes. The Illumina Clinical Services Laboratory offers a WGS test for patients with suspected rare and undiagnosed genetic disease and regularly submits potential candidate genes to GM to strengthen gene–disease relationships. We describe our experience with GM, including criteria for evaluation of candidate genes, and our workflow for the submission and review process. We have made 69 submissions, 36 of which are currently active. Ten percent of submissions have resulted in publications, with an additional 14 submissions part of ongoing collaborations and expected to result in a publication.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse ...population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% 195/345 vs. HIC 33.5% 221/659, OR 2.6, 95% CI 1.9–3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1–∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5–1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.
iHope provided clinical genome testing to a global population of 1,004 underserved individuals with suspected rare genetic disease. Diagnostic yield, and the proportion with a change of management, was >40% for individuals from both low- and middle-income or high-income countries, suggesting that widespread availability of genomic testing may reduce health disparities.
The relative amount of
14C in a sample of atmospheric particulate matter (PM), defined as percent modern carbon (pMC), allows the Environmental Protection Agency (EPA) to infer the fraction of PM ...derived from anthropogenic pollution sources. With increased use of biofuels that contain
14C, the main assumption of the two-source model, that
14C is solely derived from biogenic emissions, may become invalid. The goal of this study was to determine the
14C content of PM emitted from an off-highway diesel engine running on commercial grade biodiesel.
Tests were conducted with an off-highway diesel engine running at 80% load fueled by various blends of soy-based biodiesel. A dilution tunnel was used to collect PM
10 emissions on quartz filters that were analyzed for their
14C content using accelerator mass spectrometry. A mobility particle sizer and 5-gas analyzer provided supporting information on the particle size distribution and gas-phase emissions.
The pMC of PM
10 aerosol increased linearly with the percentage of biodiesel present in the fuel. Therefore, PM emissions resulting from increased combustion of biodiesel fuels will likely affect contemporary
14C apportionment efforts that attempt to split biogenic vs. anthropogenic emissions based on aerosol-
14C content. Increasing the biodiesel fuel content also reduced emissions of total hydrocarbons (THC), PM
10 mass, and particulate elemental carbon. Biodiesel had variable results on oxides of nitrogen
(
NO
x
)
emissions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The topic of autism has been gradually emerging as a primary focus for research, education, charities, etc. Much of the attention has been centered on children; however, the subject of adults with ...autism has long been overlooked. Adults with autism need policy improvements to help gain as much independence in their daily lives as possible. It is the purpose of this thesis to identify deficiencies in service delivery and recommend policies to improve the quality of life of adults with autism. I will utilize a cross-sectional multiple case study design. Three private foundations are utilized as the case studies, along with interviews of elites associated in or around these organizations as well as in state government. Previous literature and policies will be reviewed and integrated into the research garnered from the case studies. Following, the information will be synthesized, using John Kingdon's model of Multiple Streams, into viable policy recommendations.
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