scholarly journals Separating the signal from the noise in metagenomic cell-free DNA sequencing

2019 ◽  
Author(s):  
Philip Burnham ◽  
Nardhy Gomez-Lopez ◽  
Michael Heyang ◽  
Alexandre Pellan Cheng ◽  
Joan Sesing Lenz ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
High Throughput Sequencing ◽  
False Positive Rate ◽  
Normal Pregnancy ◽  
True Positive Rate ◽  
Total Biomass ◽  
Metagenomic Sequencing ◽  
Cell Free Dna ◽  
Free Dna ◽  
Positive Rate

Abstract Background: Cell-free DNA (cfDNA) in blood, urine and other biofluids provides a unique window into human health. A proportion of cfDNA is derived from bacteria and viruses, creating opportunities for the diagnosis of infection via metagenomic sequencing. The total biomass of microbial-derived cfDNA in clinical isolates is low, which makes metagenomic cfDNA sequencing susceptible to contamination and alignment noise. Results: Here, we report Low Biomass Background Correction (LBBC), a bioinformatics noise filtering tool informed by the uniformity of the coverage of microbial genomes and the batch variation in the absolute abundance of microbial cfDNA. We demonstrate that LBBC leads to a dramatic reduction in false positive rate while minimally affecting the true positive rate for a cfDNA test to screen for urinary tract infection. We next performed high throughput sequencing of cfDNA in amniotic fluid collected from term uncomplicated pregnancies or those complicated with clinical chorioamnionitis with and without intra-amniotic infection. Conclusions: The data provide unique insight into the properties of fetal and maternal cfDNA in amniotic fluid, demonstrate the utility of cfDNA to screen for intra-amniotic infection, support the view that the amniotic fluid is sterile during normal pregnancy, and reveal cases of intra-amniotic inflammation without infection at term.

scholarly journals Separating the signal from the noise in metagenomic cell-free DNA sequencing

2020 ◽  
Author(s):  
Philip Burnham ◽  
Nardhy Gomez-Lopez ◽  
Michael Heyang ◽  
Alexandre Pellan Cheng ◽  
Joan Sesing Lenz ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
High Throughput Sequencing ◽  
False Positive Rate ◽  
Normal Pregnancy ◽  
True Positive Rate ◽  
Total Biomass ◽  
Metagenomic Sequencing ◽  
Cell Free Dna ◽  
Free Dna ◽  
Positive Rate

Abstract Background: Cell-free DNA (cfDNA) in blood, urine and other biofluids provides a unique window into human health. A proportion of cfDNA is derived from bacteria and viruses, creating opportunities for the diagnosis of infection via metagenomic sequencing. The total biomass of microbial-derived cfDNA in clinical isolates is low, which makes metagenomic cfDNA sequencing susceptible to contamination and alignment noise. Results: Here, we report Low Biomass Background Correction (LBBC), a bioinformatics noise filtering tool informed by the uniformity of the coverage of microbial genomes and the batch variation in the absolute abundance of microbial cfDNA. We demonstrate that LBBC leads to a dramatic reduction in false positive rate while minimally affecting the true positive rate for a cfDNA test to screen for urinary tract infection. We next performed high throughput sequencing of cfDNA in amniotic fluid collected from term uncomplicated pregnancies or those complicated with clinical chorioamnionitis with and without intra-amniotic infection. Conclusions: The data provide unique insight into the properties of fetal and maternal cfDNA in amniotic fluid, demonstrate the utility of cfDNA to screen for intra-amniotic infection, support the view that the amniotic fluid is sterile during normal pregnancy, and reveal cases of intra-amniotic inflammation without infection at term.

scholarly journals Separating the signal from the noise in metagenomic cell-free DNA sequencing

2019 ◽  
Author(s):  
Philip Burnham ◽  
Nardhy Gomez-Lopez ◽  
Michael Heyang ◽  
Alexandre Pellan Cheng ◽  
Joan Sesing Lenz ◽  
...  
Keyword(s):  
Amniotic Fluid ◽  
High Throughput Sequencing ◽  
False Positive Rate ◽  
Normal Pregnancy ◽  
True Positive Rate ◽  
Total Biomass ◽  
Metagenomic Sequencing ◽  
Cell Free Dna ◽  
Free Dna ◽  
Positive Rate

ABSTRACTCell-free DNA (cfDNA) in blood, urine and other biofluids provides a unique window into human health. A proportion of cfDNA is derived from bacteria and viruses, creating opportunities for the diagnosis of infection via metagenomic sequencing. The total biomass of microbial-derived cfDNA in clinical isolates is low, which makes metagenomic cfDNA sequencing susceptible to contamination and alignment noise. Here, we report Low Biomass Background Correction (LBBC), a bioinformatics noise filtering tool informed by the uniformity of the coverage of microbial genomes and the batch variation in the absolute abundance of microbial cfDNA. We demonstrate that LBBC leads to a dramatic reduction in false positive rate while minimally affecting the true positive rate for a cfDNA test to screen for urinary tract infection. We next performed high throughput sequencing of cfDNA in amniotic fluid collected from term uncomplicated pregnancies or those complicated with clinical chorioamnionitis with and without intra-amniotic infection. The data provide unique insight into the properties of fetal and maternal cfDNA in amniotic fluid, demonstrate the utility of cfDNA to screen for intra-amniotic infection, support the view that the amniotic fluid is sterile during normal pregnancy, and reveal cases of intra-amniotic inflammation without infection at term.

scholarly journals A cell-free DNA metagenomic sequencing assay that integrates the damage response to infection

2019 ◽  
Author(s):  
Alexandre Pellan Cheng ◽  
Philip Burnham ◽  
John Richard Lee ◽  
Matthew Pellan Cheng ◽  
Manikkam Suthanthiran ◽  
...  
Keyword(s):  
Urinary Tract ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Viral Infections ◽  
Clinical Samples ◽  
Metagenomic Sequencing ◽  
Kidney Transplant Recipients ◽  
Bladder Tissue ◽  
Cell Free Dna ◽  
Free Dna

ABSTRACTHigh-throughput metagenomic sequencing offers an unbiased approach to identify pathogens in clinical samples. Conventional metagenomic sequencing however does not integrate information about the host, which is often critical to distinguish infection from infectious disease, and to assess the severity of disease. Here, we explore the utility of high-throughput sequencing of cell-free DNA after bisulfite conversion to map the tissue and cell types of origin of host-derived cell-free DNA, and to profile the bacterial and viral metagenome. We applied this assay to 51 urinary cfDNA isolates collected from a cohort of kidney transplant recipients with and without bacterial and viral infection of the urinary tract. We find that the cell and tissue types of origin of urinary cell-free DNA can be derived from its genome-wide profile of methylation marks, and strongly depend on infection status. We find evidence of kidney and bladder tissue damage due to viral and bacterial infection, respectively, and of the recruitment of neutrophils to the urinary tract during infection. Through direct comparison to conventional metagenomic sequencing as well as clinical tests of infection, we find this assay accurately captures the bacterial and viral composition of the sample. The assay presented here is straightforward to implement, offers a systems view into bacterial and viral infections of the urinary tract, and can find future use as a tool for the differential diagnosis of infections.

scholarly journals A cell-free DNA metagenomic sequencing assay that integrates the host injury response to infection

2019 ◽  
Vol 116 (37) ◽  
pp. 18738-18744 ◽  
Author(s):  
Alexandre Pellan Cheng ◽  
Philip Burnham ◽  
John Richard Lee ◽  
Matthew Pellan Cheng ◽  
Manikkam Suthanthiran ◽  
...  
Keyword(s):  
Urinary Tract ◽  
High Throughput ◽  
High Throughput Sequencing ◽  
Viral Infections ◽  
Clinical Samples ◽  
Metagenomic Sequencing ◽  
Kidney Transplant Recipients ◽  
Bladder Tissue ◽  
Cell Free Dna ◽  
Free Dna

High-throughput metagenomic sequencing offers an unbiased approach to identify pathogens in clinical samples. Conventional metagenomic sequencing, however, does not integrate information about the host, which is often critical to distinguish infection from infectious disease, and to assess the severity of disease. Here, we explore the utility of high-throughput sequencing of cell-free DNA (cfDNA) after bisulfite conversion to map the tissue and cell types of origin of host-derived cfDNA, and to profile the bacterial and viral metagenome. We applied this assay to 51 urinary cfDNA isolates collected from a cohort of kidney transplant recipients with and without bacterial and viral infection of the urinary tract. We find that the cell and tissue types of origin of urinary cfDNA can be derived from its genome-wide profile of methylation marks, and strongly depend on infection status. We find evidence of kidney and bladder tissue damage due to viral and bacterial infection, respectively, and of the recruitment of neutrophils to the urinary tract during infection. Through direct comparison to conventional metagenomic sequencing as well as clinical tests of infection, we find this assay accurately captures the bacterial and viral composition of the sample. The assay presented here is straightforward to implement, offers a systems view into bacterial and viral infections of the urinary tract, and can find future use as a tool for the differential diagnosis of infection.

scholarly journals False-Positive Rate in First-Trimester Screening Based on Ultrasound and Cell-Free DNA versus First-Trimester Combined Screening with Additional Ultrasound Markers

2018 ◽  
Vol 45 (5) ◽  
pp. 317-324
Author(s):  
Karl Oliver Kagan ◽  
Vanessa Maier ◽  
Jiri Sonek ◽  
Harald Abele ◽  
Kai Lüthgens ◽  
...  
Keyword(s):  
False Positive ◽  
False Positive Rate ◽  
First Trimester ◽  
First Trimester Screening ◽  
Cell Free Dna ◽  
Free Dna ◽  
Positive Rate ◽  
Trimester Screening

scholarly journals PRATD: A Phased Remote Access Trojan Detection Method with Double-Sided Features

Electronics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1894
Author(s):  
Chun Guo ◽  
Zihua Song ◽  
Yuan Ping ◽  
Guowei Shen ◽  
Yuhei Cui ◽  
...  
Keyword(s):  
False Positive ◽  
Detection Method ◽  
False Positive Rate ◽  
True Positive Rate ◽  
Remote Access ◽  
Detection Methods ◽  
Security Threats ◽  
True Positive ◽  
Trojan Detection ◽  
Positive Rate

Remote Access Trojan (RAT) is one of the most terrible security threats that organizations face today. At present, two major RAT detection methods are host-based and network-based detection methods. To complement one another’s strengths, this article proposes a phased RATs detection method by combining double-side features (PRATD). In PRATD, both host-side and network-side features are combined to build detection models, which is conducive to distinguishing the RATs from benign programs because that the RATs not only generate traffic on the network but also leave traces on the host at run time. Besides, PRATD trains two different detection models for the two runtime states of RATs for improving the True Positive Rate (TPR). The experiments on the network and host records collected from five kinds of benign programs and 20 famous RATs show that PRATD can effectively detect RATs, it can achieve a TPR as high as 93.609% with a False Positive Rate (FPR) as low as 0.407% for the known RATs, a TPR 81.928% and FPR 0.185% for the unknown RATs, which suggests it is a competitive candidate for RAT detection.

Ascertaining an efficient eligibility cut-off for extended Medicare items for eating disorders

2021 ◽  
pp. 103985622110286
Author(s):  
Tracey Wade ◽  
Jamie-Lee Pennesi ◽  
Yuan Zhou
Keyword(s):  
Eating Disorders ◽  
Eating Disorder ◽  
False Positive Rate ◽  
Area Under The Curve ◽  
Rate Sensitivity ◽  
True Positive Rate ◽  
Eating Disorder Examination Questionnaire ◽  
Eating Disorder Examination ◽  
Positive Rate ◽  
The Relationship

Objective: Currently eligibility for expanded Medicare items for eating disorders (excluding anorexia nervosa) require a score ⩾ 3 on the 22-item Eating Disorder Examination-Questionnaire (EDE-Q). We compared these EDE-Q “cases” with continuous scores on a validated 7-item version of the EDE-Q (EDE-Q7) to identify an EDE-Q7 cut-off commensurate to 3 on the EDE-Q. Methods: We utilised EDE-Q scores of female university students ( N = 337) at risk of developing an eating disorder. We used a receiver operating characteristic (ROC) curve to assess the relationship between the true-positive rate (sensitivity) and the false-positive rate (1-specificity) of cases ⩾ 3. Results: The area under the curve showed outstanding discrimination of 0.94 (95% CI: .92–.97). We examined two specific cut-off points on the EDE-Q7, which included 100% and 87% of true cases, respectively. Conclusion: Given the EDE-Q cut-off for Medicare is used in conjunction with other criteria, we suggest using the more permissive EDE-Q7 cut-off (⩾2.5) to replace use of the EDE-Q cut-off (⩾3) in eligibility assessments.

scholarly journals Improving Ecological Inference by Predicting Individual Ethnicity from Voter Registration Records

2016 ◽  
Vol 24 (2) ◽  
pp. 263-272 ◽  
Author(s):  
Kosuke Imai ◽  
Kabir Khanna
Keyword(s):  
Mean Squared Error ◽  
False Positive Rate ◽  
True Positive Rate ◽  
Voter Registration ◽  
Racial Groups ◽  
Ecological Inference ◽  
Inference Problem ◽  
Individual Level ◽  
Positive Rate ◽  
Election Results

In both political behavior research and voting rights litigation, turnout and vote choice for different racial groups are often inferred using aggregate election results and racial composition. Over the past several decades, many statistical methods have been proposed to address this ecological inference problem. We propose an alternative method to reduce aggregation bias by predicting individual-level ethnicity from voter registration records. Building on the existing methodological literature, we use Bayes's rule to combine the Census Bureau's Surname List with various information from geocoded voter registration records. We evaluate the performance of the proposed methodology using approximately nine million voter registration records from Florida, where self-reported ethnicity is available. We find that it is possible to reduce the false positive rate among Black and Latino voters to 6% and 3%, respectively, while maintaining the true positive rate above 80%. Moreover, we use our predictions to estimate turnout by race and find that our estimates yields substantially less amounts of bias and root mean squared error than standard ecological inference estimates. We provide open-source software to implement the proposed methodology.

Is there still a rationale for non-invasive PGT-A by analysis of cell-free DNA released by human embryos into culture medium?

2021 ◽  
Vol 36 (5) ◽  
pp. 1186-1190
Author(s):  
Raoul Orvieto ◽  
Adva Aizer ◽  
Norbert Gleicher
Keyword(s):  
Culture Media ◽  
Chromosomal Rearrangements ◽  
Primary Source ◽  
Normal Pregnancy ◽  
Early Embryo ◽  
Human Embryos ◽  
Cell Debris ◽  
Cell Free Dna ◽  
Non Invasive ◽  
Free Dna

Abstract Human embryos utilise an array of processes to eliminate the very high prevalence of aneuploid cells in early embryo stages. Human embryo self-correction was recently demonstrated by their ability to eliminate/expel abnormal blastomeres as cell debris/fragments. A whole genome amplification study has demonstrated that 63.6% of blastocysts expelled cell debris with abnormal chromosomal rearrangements. Moreover, 55.5% of euploid blastocysts expel aneuploid debris, strongly suggesting that the primary source of cell free DNA in culture media is expelled aneuploid blastomeres and/or their fragments. Such a substantial ability to self-correct downstream from the blastocyststage, therefore, renders any chromosomal diagnosis at the blastocyststage potentially useless, and this, unfortunately, also must particularly include non-invasive PGT-A based on cell-free DNA in spent medium. High rates of false-positive diagnoses of human embryos often lead to non-use and/or disposal of embryos with entirely normal pregnancy potential. Before adopting yet another round of unvalidated PGT-A as a routine adjunct to IVF, we here present facts that deserve to be considered.

Watch For Failing Objects: What Inappropriate Compliance Reveals About Shared Mental Models In Autonomous Cars

2021 ◽  
Vol 65 (1) ◽  
pp. 643-647
Author(s):  
Yosef S. Razin ◽  
Jack Gale ◽  
Jiaojiao Fan ◽  
Jaznae’ Smith ◽  
Karen M. Feigh
Keyword(s):  
Mental Models ◽  
Mental Model ◽  
False Positive Rate ◽  
Ground Truth ◽  
True Positive Rate ◽  
Shared Mental Models ◽  
Shared Mental Model ◽  
Autonomous Cars ◽  
Positive Rate ◽  
Dispositional Factors

This paper evaluates Banks et al.’s Human-AI Shared Mental Model theory by examining how a self-driving vehicle’s hazard assessment facilitates shared mental models. Participants were asked to affirm the vehicle’s assessment of road objects as either hazards or mistakes in real-time as behavioral and subjective measures were collected. The baseline performance of the AI was purposefully low (<50%) to examine how the human’s shared mental model might lead to inappropriate compliance. Results indicated that while the participant true positive rate was high, overall performance was reduced by the large false positive rate, indicating that participants were indeed being influenced by the Al’s faulty assessments, despite full transparency as to the ground-truth. Both performance and compliance were directly affected by frustration, mental, and even physical demands. Dispositional factors such as faith in other people’s cooperativeness and in technology companies were also significant. Thus, our findings strongly supported the theory that shared mental models play a measurable role in performance and compliance, in a complex interplay with trust.

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