Use of performance-monitoring to improve reliability of emergency diesel generators

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Nuclear Engineering, 1998.Includes bibliographical references (p. 149-151).Emergency diesel generators are one of the most important contributors to the core damage failure rate of nuclear power plants. Current required testing and maintenance procedures are excessively strict and expensive without any real justification. Probabilistic risk assessment is used to propose a monitoring system and Technical Specification changes to reduce EDG unavailability without jeopardizing safety, and to ease the excessive deterministic requirements. The EDG fault tree is analyzed to identify the critical failure modes of the EDG, the failure of service water pumps, the failure of EDG building ventilation dampers, and the failure of the EDG "supercomponent," which includes the fuel oil, lubricating oil, cooling water, and starting air systems. We use data from the nuclear industry and the U.S. Navy to identify the most significant EDG supercomponent failure modes, including system fluid leakages, instrumentation & controls failures, electrical power output failures, and the fuel system governors. The monitoring system proposed includes instrumentation for twenty-one of the 121 basic events in the fault tree, for a total of 94.9% of EDG failure contributions. The failure modes identified with industry data are monitored, as are diesel engine mechanical failures currently assessed with teardown inspections. With a 50% reduction in these twenty-one basic event failure rates, the EDG system failure rate is reduced by 41.6%, from 0.097 per year to 0.059 per year. With this reduced failure rate, we propose to extend the EDG surveillance interval from one month to twelve months, to lengthen the running tests from one hour to twenty-four hours, and to eliminate the tear-down inspections conducted during refueling outages. To fully assess the benefits of these proposed changes, the monitoring system should be installed on an EDG on a trial basis. The work reported here demonstrates the feasible gains which can be realized, and proposes, a method for evaluating the efficacy of the system as realized through experimentation.by Jeffrey D. Dulik.S.M

Performance of ACMG-AMP Variant-Interpretation Guidelines among Nine Laboratories in the Clinical Sequencing Exploratory Research Consortium

Evaluating the pathogenicity of a variant is challenging given the plethora of types of genetic evidence that laboratories consider. Deciding how to weigh each type of evidence is difficult, and standards have been needed. In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) published guidelines for the assessment of variants in genes associated with Mendelian diseases. Nine molecular diagnostic laboratories involved in the Clinical Sequencing Exploratory Research (CSER) consortium piloted these guidelines on 99 variants spanning all categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign). Nine variants were distributed to all laboratories, and the remaining 90 were evaluated by three laboratories. The laboratories classified each variant by using both the laboratory's own method and the ACMG-AMP criteria. The agreement between the two methods used within laboratories was high (K-alpha = 0.91) with 79% concordance. However, there was only 34% concordance for either classification system across laboratories. After consensus discussions and detailed review of the ACMG-AMP criteria, concordance increased to 71%. Causes of initial discordance in ACMG-AMP classifications were identified, and recommendations on clarification and increased specification of the ACMG-AMP criteria were made. In summary, although an initial pilot of the ACMG-AMP guidelines did not lead to increased concordance in variant interpretation, comparing variant interpretations to identify differences and having a common framework to facilitate resolution of those differences were beneficial for improving agreement, allowing iterative movement toward increased reporting consistency for variants in genes associated with monogenic disease

The GenoChip: A New Tool for Genetic Anthropology

The Genographic Project is an international effort aimed at charting human migratory history. The project is nonprofit and nonmedical, and, through its Legacy Fund, supports locally led efforts to preserve indigenous and traditional cultures. Although the first phase of the project was focused on uniparentally inherited markers on the Y-chromosome and mitochondrial DNA (mtDNA), the current phase focuses on markers from across the entire genome to obtain a more complete understanding of human genetic variation. Although many commercial arrays exist for genome-wide single-nucleotide polymorphism (SNP) genotyping, they were designed for medical genetic studies and contain medically related markers that are inappropriate for global population genetic studies. GenoChip, the Genographic Project’s new genotyping array, was designed to resolve these issues and enable higher resolution research into outstanding questions in genetic anthropology. TheGenoChip includes ancestry informativemarkers obtained for over 450 human populations, an ancient human (Saqqaq), and two archaic hominins (Neanderthal and Denisovan) and was designed to identify all knownY-chromosome andmtDNAhaplogroups. The chip was carefully vetted to avoid inclusion ofmedically relevant markers. To demonstrate its capabilities, we compared the FST distributions of GenoChip SNPs to those of two commercial arrays. Although all arrays yielded similarly shaped (inverse J) FST distributions, the GenoChip autosomal and X-chromosomal distributions had the highestmean FST, attesting to its ability to discern subpopulations. The chip performances are illustrated in a principal component analysis for 14 worldwide populations. In summary, the GenoChip is a dedicated genotyping platform for genetic anthropology. With an unprecedented number of approximately 12,000 Y-chromosomal and approximately 3,300 mtDNA SNPs and over 130,000 autosomal and X-chromosomal SNPswithout any known health,medical, or phenotypic relevance, the GenoChip is a useful tool for genetic anthropology and population genetics

Dissecting the Within-Africa Ancestry of Populations of African Descent in the Americas

The ancestry of African-descended Americans is known to be drawn from three distinct populations: African, European, and Native American. While many studies consider this continental admixture, few account for the genetically distinct sources of ancestry within Africa--the continent with the highest genetic variation. Here, we dissect the within-Africa genetic ancestry of various populations of the Americas self-identified as having primarily African ancestry using uniparentally inherited mitochondrial DNA.We first confirmed that our results obtained using uniparentally-derived group admixture estimates are correlated with the average autosomal-derived individual admixture estimates (hence are relevant to genomic ancestry) by assessing continental admixture using both types of markers (mtDNA and Y-chromosome vs. ancestry informative markers). We then focused on the within-Africa maternal ancestry, mining our comprehensive database of published mtDNA variation (∼5800 individuals from 143 African populations) that helped us thoroughly dissect the African mtDNA pool. Using this well-defined African mtDNA variation, we quantified the relative contributions of maternal genetic ancestry from multiple W/WC/SW/SE (West to South East) African populations to the different pools of today's African-descended Americans of North and South America and the Caribbean.Our analysis revealed that both continental admixture and within-Africa admixture may be critical to achieving an adequate understanding of the ancestry of African-descended Americans. While continental ancestry reflects gender-specific admixture processes influenced by different socio-historical practices in the Americas, the within-Africa maternal ancestry reflects the diverse colonial histories of the slave trade. We have confirmed that there is a genetic thread connecting Africa and the Americas, where each colonial system supplied their colonies in the Americas with slaves from African colonies they controlled or that were available for them at the time. This historical connection is reflected in different relative contributions from populations of W/WC/SW/SE Africa to geographically distinct Africa-derived populations of the Americas, adding to the complexity of genomic ancestry in groups ostensibly united by the same demographic label

Actionable exomic incidental findings in 6503 participants: challenges of variant classification

Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Use of Performance Monitoring to Improve Reliability of Emergency Generators Diesel

Emergency diesel generators are one of the most important contributors to the core damage failure rate of nuclear power plants. Current required testing and maintenance procedures are excessively strict and expensive without any real justification. Probabilistic risk assessment is used to propose a monitoring system and Technical Specification changes to reduce EDG unavailability without jeopardizing safety, and to ease the excessive deterministic requirements. The EDG fault tree is analyzed to identify the critical failure modes of the EDG, the failure of service water pumps, the failure of EDG building ventilation dampers, and the failure of the EDG "supercomponent," which includes the fuel oil, lubricating oil, cooling water, and starting air systems. We use data from the nuclear industry and the U.S. Navy to identify the most significant EDG supercomponent failure modes, including system fluid leakages, instrumentation & controls failures, electrical power output failures, and the fuel system governors. The monitoring system proposed includes instrumentation for twenty-one of the 121 basic events in the fault tree, for a total of 94.9% of EDG failure contributions. The failure modes identified with industry data are monitored, as are diesel engine mechanical failures currently assessed with teardown inspections. With a 50% reduction in these twenty-one basic event failure rates, the EDG system failure rate is reduced by 41.6%, from 0.097 per year to 0.059 per year. With this reduced failure rate, we propose to extend the EDG surveillance interval from one month to twelve months, to lengthen the running tests from one hour to twenty-four hours, and to eliminate the tear-down inspections conducted during refueling outages. To fully assess the benefits of these proposed changes, the monitoring system should be installed on an EDG on a trial basis. The work reported here demonstrates the feasible gains which can be realized, and proposes, a method for evaluating the efficacy of the system as realized through experimentation.Institute of Nuclear Power OperationsIdaho National Engineering and Environmental Laborator