scholarly journals Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders

2020 ◽  
Author(s):  
Yan Sun ◽  
Fengxia Liu ◽  
Chunna Fan ◽  
Yaoshen Wang ◽  
Lijie Song ◽  
...  
Keyword(s):  
Diagnostic Test ◽  
Genetic Disorders ◽  
Lower Sensitivity ◽  
Current Standard ◽  
Indel Detection ◽  
Detection And Identification ◽  
The Family ◽  
Family Based ◽  
Disease Associated Genes ◽  
Clinical Cases

Abstract Background: Due to its reduced cost and incomparable advantages, WGS is likely to lead to changes in clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated. Here, the performance of WGS in NA12878, the YH cell line, and the Chinese trios were measured by assessing their sensitivity, PPV, depth and breadth of coverage using MGISEQ-2000. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using the family-based trio design for the Chinese trios. We further developed a systematic WGS pipeline for the analysis of 8 clinical cases. Results: In general, the sensitivity and PPV for SNV/indel detection increased with mean depth and reached a plateau at an ~40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozygous and heterozygous SNPs of NA12878 was >99.25% and >99.50%, respectively, and the PPV was 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV were still not 100% even with a mean depth of ~150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size less than 1 kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~40X) was better than WES (~120X). Among the Chinese trios with an ~40X mean depth, the sensitivity among offspring was >99.48% and >96.36% for SNP and indel detection, and the PPVs were 99.86% and 97.93%. All 12 previously validated variants in the 8 clinical cases were successfully detected using our WGS pipeline.Conclusions: The current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. It would be advisable for clinical scientists to determine the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports.

scholarly journals Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yan Sun ◽  
Fengxia Liu ◽  
Chunna Fan ◽  
Yaoshen Wang ◽  
Lijie Song ◽  
...  
Keyword(s):  
Diagnostic Test ◽  
Genetic Disorders ◽  
Lower Sensitivity ◽  
Current Standard ◽  
Indel Detection ◽  
Detection And Identification ◽  
The Family ◽  
Family Based ◽  
Disease Associated Genes ◽  
Clinical Cases

Abstract Background Due to its reduced cost and incomparable advantages, WGS is likely to lead to changes in clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated. Methods Here, the performance of WGS in NA12878, the YH cell line, and the Chinese trios were measured by assessing their sensitivity, PPV, depth and breadth of coverage using MGISEQ-2000. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using the family-based trio design for the Chinese trios. We further developed a systematic WGS pipeline for the analysis of 8 clinical cases. Results In general, the sensitivity and PPV for SNV/indel detection increased with mean depth and reached a plateau at an ~ 40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozygous and heterozygous SNPs of NA12878 was > 99.25% and > 99.50%, respectively, and the PPV was 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV were still not 100% even with a mean depth of ~ 150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size less than 1 kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~ 40X) was better than WES (~ 120X). Among the Chinese trios with an ~ 40X mean depth, the sensitivity among offspring was > 99.48% and > 96.36% for SNP and indel detection, and the PPVs were 99.86% and 97.93%. All 12 previously validated variants in the 8 clinical cases were successfully detected using our WGS pipeline. Conclusions The current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. It would be advisable for clinical scientists to determine the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports.

scholarly journals Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders

2020 ◽  
Author(s):  
Yan Sun ◽  
Fengxia Liu ◽  
Chunna Fan ◽  
Yaoshen Wang ◽  
Lijie Song ◽  
...  
Keyword(s):  
Diagnostic Test ◽  
Genetic Disorders ◽  
Lower Sensitivity ◽  
Current Standard ◽  
Indel Detection ◽  
Detection And Identification ◽  
Family Based ◽  
Disease Associated Genes ◽  
Cnv Detection ◽  
Clinical Cases

Abstract Background With the reduce of cost and incomparable advantages, WGS is likely to change the way of clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated, especially for CNV detection. All the samples underwent WGS using MGISEQ-2000. The performance of NA12878, YH cell line, and the Chinese trios were measured for sensitivity, PPV, depth and breadth of coverage. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using family-based trio design in the Chinese trios. We also developed a systematic WGS pipeline for the analysis of 8 clinical cases with known disease-causing variants. Results In general, the sensitivity and PPV for SNV/indel detection increased with mean depth, and reached a plateau at a ~ 40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozyous and heterozygous SNPs of NA12878 was > 99.25% and > 99.50% respectively, and PPVs were 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV is still not 100% even with a mean depth of ~ 150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size of less than 1 kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~ 40X) is better than WES (~ 120X). Among the Chinese trios with ~ 40X mean depth, the sensitivity in the offspring was > 99.48% and > 96.36% for SNP and indel detection, and PPVs were 99.86% and 97.93%. All the 12 previously validated variants in the 8 clinical cases were successfully detected by our WGS pipeline. Conclusions The current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. Clinical scientists should know the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports.

scholarly journals Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders

2020 ◽  
Author(s):  
Yan Sun ◽  
Fengxia Liu ◽  
Chunna Fan ◽  
Yaoshen Wang ◽  
Lijie Song ◽  
...  
Keyword(s):  
Diagnostic Test ◽  
Genetic Disorders ◽  
Lower Sensitivity ◽  
Current Standard ◽  
Indel Detection ◽  
Detection And Identification ◽  
Family Based ◽  
Disease Associated Genes ◽  
Cnv Detection ◽  
Clinical Cases

AbstractBackgroundWith the reduce of cost and incomparable advantages, WGS is likely to change the way of clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated, especially for CNV detection.MethodsAll the samples underwent WGS using MGISEQ-2000. The performance of NA12878, YH cell line, and the Chinese trios were measured for sensitivity, PPV, depth and breadth of coverage. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using family-based trio design in the Chinese trios. We also developed a systematic WGS pipeline for the analysis of 8 clinical cases with known disease-causing variants.ResultsIn general, the sensitivity and PPV for SNV/indel detection increased with mean depth, and reached a plateau at a ~40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozyous and heterozygous SNPs of NA12878 was >99.25% and >99.50% respectively, and PPVs were 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV is still not 100% even with a mean depth of ~150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size of less than 1kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~40X) is better than WES (~120X). Among the Chinese trios with ~40X mean depth, the sensitivity in the offspring was >99.48% and >96.36% for SNP and indel detection, and PPVs were 99.86% and 97.93%. All the 12 previously validated variants in the 8 clinical cases were successfully detected by our WGS pipeline.ConclusionsThe current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. Clinical scientists should know the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports.

scholarly journals Six shades lighter: a bit-serial implementation of the AES family

2021 ◽  
Author(s):  
Sergio Roldán Lombardía ◽  
Fatih Balli ◽  
Subhadeep Banik
Keyword(s):  
Block Cipher ◽  
Block Ciphers ◽  
Authenticated Encryption ◽  
Current Standard ◽  
Asic Circuit ◽  
The Family ◽  
Encryption And Decryption ◽  
Preliminary Version ◽  
Reduction In Area ◽  
Bit Serial

AbstractRecently, cryptographic literature has seen new block cipher designs such as , or that aim to be more lightweight than the current standard, i.e., . Even though family of block ciphers were designed two decades ago, they still remain as the de facto encryption standard, with being the most widely deployed variant. In this work, we revisit the combined one-in-all implementation of the family, namely both encryption and decryption of each as a single ASIC circuit. A preliminary version appeared in Africacrypt 2019 by Balli and Banik, where the authors design a byte-serial circuit with such functionality. We improve on their work by reducing the size of the compact circuit to 2268 GE through 1-bit-serial implementation, which achieves 38% reduction in area. We also report stand-alone bit-serial versions of the circuit, targeting only a subset of modes and versions, e.g., and . Our results imply that, in terms of area, and can easily compete with the larger members of recently designed family, e.g., , . Thus, our implementations can be used interchangeably inside authenticated encryption candidates such as , or in place of .

Separating the Contributions in Localization Methods: A Technique to Enhance Identification of Damping Related Parameters

1999 ◽  
Author(s):  
Hervé Algrain ◽  
Calogero Conti ◽  
Pierre Dehombreux
Keyword(s):  
Finite Element ◽  
Model Updating ◽  
Element Model ◽  
Dynamic Responses ◽  
Finite Element Model Updating ◽  
Global Localization ◽  
Localization Method ◽  
The Family ◽  
Family Based ◽  
The Stability

Abstract Finite Element Model Updating has for objective to increase the correlation between the experimental dynamic responses of a structure and the predictions from a model. Among different initial choices, these procedures need to establish a set of representative parameters to be updated in which some are in real error and some are not. It is therefore important to select the correct properties that have to be updated to ensure that no marginal corrections are introduced. In this paper the standard localization criteria are presented and a technique to separate the global localization criteria in family-based criteria for damped structures is introduced. The methods are analyzed and applied to both numerical and experimental examples; a clear enhancement of the results is noticed using the family-based criteria. A simple way to qualify the stability of a localization method to noise is presented.

The SNP rs560426 Within ABCA4-ARHGAP29 Locus and the Risk of Nonsyndromic Oral Clefts

2020 ◽  
Vol 57 (6) ◽  
pp. 671-677 ◽  
Author(s):  
Yah-Huei Wu-Chou ◽  
Kuo-Ting Philip Chen ◽  
Yi-Chieh Lu ◽  
Yin-Ting Lin ◽  
Hsien-Fang Chang ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Cleft Lip ◽  
Strong Association ◽  
Nucleotide Polymorphisms ◽  
Test Analysis ◽  
Oral Clefts ◽  
The Family ◽  
Abca4 Gene ◽  
Family Based ◽  
New Evidence

Objective: Nonsyndromic oral clefts are common birth defect with complex etiology. In the present study, we attempt to further validate the possible role for ABCA4 and ARHGAP29 in the susceptibility to nonsyndromic oral clefts. Design: We performed allelic transmission disequilibrium test analysis, on 10 eligible single nucleotide polymorphisms (SNPs) and SNP haplotypes using the Family-Based Association Test. Participants: The study sample consisted of 334 case–parent trios of nonsyndromic oral clefts from Taiwanese population, separated into nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) groups. Results: We found only the SNP rs560426 within the ABCA4 gene showed strong association with NSCPO ( P = .03498; Permuted P = .05382). No association between other 9 selected SNPs in ABCA4-ARHGAP29 region and the risk of nonsyndromic oral clefts was found. For the haplotype analyses, we found only haplotype T-C (rs570926 and rs3789431) in ABCA4 block 2 showed significant association with nonsyndromic NSCL/P in these Taiwanese trios. Conclusions: We used a family-based analysis in 334 Taiwanese case–parent trios to validate the possible role for ABCA4 and ARHGAP29 in the susceptibility to nonsyndromic oral clefts. This study provides a new evidence for an association between the intron variant rs560426 within ABCA4 and nonsyndromic cleft palate which may contribute their regulatory role in craniofacial development.

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