Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study

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Abstract

Objectives To validate the clinical efficacy and practical feasibility of massively parallel maternal plasma DNA sequencing to screen for fetal trisomy 21 among high risk pregnancies clinically indicated for amniocentesis or chorionic villus sampling.

Design Diagnostic accuracy validated against full karyotyping, using prospectively collected or archived maternal plasma samples.

Setting Prenatal diagnostic units in Hong Kong, United Kingdom, and the Netherlands.

Participants 753 pregnant women at high risk for fetal trisomy 21 who underwent definitive diagnosis by full karyotyping, of whom 86 had a fetus with trisomy 21.

Intervention Multiplexed massively parallel sequencing of DNA molecules in maternal plasma according to two protocols with different levels of sample throughput: 2-plex and 8-plex sequencing.

Main outcome measures Proportion of DNA molecules that originated from chromosome 21. A trisomy 21 fetus was diagnosed when the z score for the proportion of chromosome 21 DNA molecules was >3. Diagnostic sensitivity, specificity, positive predictive value, and negative predictive value were calculated for trisomy 21 detection.

Results Results were available from 753 pregnancies with the 8-plex sequencing protocol and from 314 pregnancies with the 2-plex protocol. The performance of the 2-plex protocol was superior to that of the 8-plex protocol. With the 2-plex protocol, trisomy 21 fetuses were detected at 100% sensitivity and 97.9% specificity, which resulted in a positive predictive value of 96.6% and negative predictive value of 100%. The 8-plex protocol detected 79.1% of the trisomy 21 fetuses and 98.9% specificity, giving a positive predictive value of 91.9% and negative predictive value of 96.9%.

Conclusion Multiplexed maternal plasma DNA sequencing analysis could be used to rule out fetal trisomy 21 among high risk pregnancies. If referrals for amniocentesis or chorionic villus sampling were based on the sequencing test results, about 98% of the invasive diagnostic procedures could be avoided.

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Most cited references 28

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Long Term Outcomes Following Hospital Admission for Sepsis Using Relative Survival Analysis: A Prospective Cohort Study of 1,092 Patients with 5 Year Follow Up

Joshua Davis, Vincent He, Nicholas Anstey … (2014)

Background Sepsis is a leading cause of death in intensive care units and is increasing in incidence. Current trials of novel therapeutic approaches for sepsis focus on 28-day mortality as the primary outcome measure, but excess mortality may extend well beyond this time period. Methods We used relative survival analysis to examine excess mortality in a cohort of 1,028 patients admitted to a tertiary referral hospital with sepsis during 2007–2008, over the first 5 years of follow up. Expected survival was estimated using the Ederer II method, using Australian life tables as the reference population. Cumulative and interval specific relative survival were estimated by age group, sex, sepsis severity and Indigenous status. Results Patients were followed for a median of 4.5 years (range 0–5.2). Of the 1028 patients, the mean age was 46.9 years, 52% were male, 228 (22.2%) had severe sepsis and 218 (21%) died during the follow up period. Mortality based on cumulative relative survival exceeded that of the reference population for the first 2 years post admission in the whole cohort and for the first 3 years in the subgroup with severe sepsis. Independent predictors of mortality over the whole follow up period were male sex, Indigenous Australian ethnicity, older age, higher Charlson Comorbidity Index, and sepsis-related organ dysfunction at presentation. Conclusions The mortality rate of patients hospitalised with sepsis exceeds that of the general population until 2 years post admission. Efforts to improve outcomes from sepsis should examine longer term outcomes than the traditional primary endpoints of 28-day and 90-day mortality.

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Preparation of Artificial Plasma Membrane Mimicking Vesicles with Lipid Asymmetry

Qingqing Lin, Erwin London (2014)

Lipid asymmetry, the difference in lipid distribution across the lipid bilayer, is one of the most important features of eukaryotic cellular membranes. However, commonly used model membrane vesicles cannot provide control of lipid distribution between inner and outer leaflets. We recently developed methods to prepare asymmetric model membrane vesicles, but facile incorporation of a highly controlled level of cholesterol was not possible. In this study, using hydroxypropyl-α-cyclodextrin based lipid exchange, a simple method was devised to prepare large unilamellar model membrane vesicles that closely resemble mammalian plasma membranes in terms of their lipid composition and asymmetry (sphingomyelin (SM) and/or phosphatidylcholine (PC) outside/phosphatidylethanolamine (PE) and phosphatidylserine (PS) inside), and in which cholesterol content can be readily varied between 0 and 50 mol%. We call these model membranes “artificial plasma membrane mimicking” (“PMm”) vesicles. Asymmetry was confirmed by both chemical labeling and measurement of the amount of externally-exposed anionic lipid. These vesicles should be superior and more realistic model membranes for studies of lipid-lipid and lipid-protein interaction in a lipid environment that resembles that of mammalian plasma membranes.

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Outcomes in Patients with Acute and Stable Coronary Syndromes; Insights from the Prospective NOBORI-2 Study

Farzin Fath-Ordoubadi, Erik Spaepen, Magdi El-Omar … (2014)

Background Contemporary data remains limited regarding mortality and major adverse cardiac events (MACE) outcomes in patients undergoing PCI for different manifestations of coronary artery disease. Objectives We evaluated mortality and MACE outcomes in patients treated with PCI for STEMI (ST-elevation myocardial infarction), NSTEMI (non ST-elevation myocardial infarction) and stable angina through analysis of data derived from the Nobori-2 study. Methods Clinical endpoints were cardiac mortality and MACE (a composite of cardiac death, myocardial infarction and target vessel revascularization). Results 1909 patients who underwent PCI were studied; 1332 with stable angina, 248 with STEMI and 329 with NSTEMI. Age-adjusted Charlson co-morbidity index was greatest in the NSTEMI cohort (3.78±1.91) and lowest in the stable angina cohort (3.00±1.69); P<0.0001. Following Cox multivariate analysis cardiac mortality was independently worse in the NSTEMI vs the stable angina cohort (HR 2.31 (1.10–4.87), p = 0.028) but not significantly different for STEMI vs stable angina cohort (HR 0.72 (0.16–3.19), p = 0.67). Similar observations were recorded for MACE (<180 days) (NSTEMI vs stable angina: HR 2.34 (1.21–4.55), p = 0.012; STEMI vs stable angina: HR 2.19 (0.97–4.98), p = 0.061. Conclusions The longer-term Cardiac mortality and MACE were significantly worse for patients following PCI for NSTEMI even after adjustment of clinical demographics and Charlson co-morbidity index whilst the longer-term prognosis of patients following PCI STEMI was favorable, with similar outcomes as those patients with stable angina following PCI.

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: Role: professor

: Role: clinical research fellow

: Role: student

: Role: professor

: Role: assistant professor

: Role: associate professor

: Role: postdoctoral fellow

: Role: professor

: Role: department manager and honorary assistant professor

: Role: consultant

: Role: obstetrician

: Role: manager

: Role: professor

: Role: postdoctoral fellow

: Role: consultant and honorary clinical associate professor

: Role: professor, Role: associate director

: Role: associate professor

: Role: professor

Journal

Journal ID (nlm-ta): BMJ

Journal ID (publisher-id): bmj

Title: BMJ : British Medical Journal

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1468-5833

Publication date Collection: 2011

Publication date (Print): 2011

Publication date (Electronic): 11 January 2011

Volume: 342

Electronic Location Identifier: c7401

Affiliations

[1 ]Centre for Research into Circulating Fetal Nucleic Acids, Li Ka Shing Institute of Health Sciences, Department of Chemical Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China

[2 ]Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong

[3 ]Harris Birthright Research Centre for Foetal Medicine, King’s College Hospital, London SE5 9RS, UK

[4 ]VU University Medical Center, 10081 HV Amsterdam, Netherlands

[5 ]Tsan Yuk Hospital, Department of Obstetrics and Gynaecology, University of Hong Kong, Hong Kong

[6 ]United Christian Hospital, Hospital Authority, Hong Kong

[7 ]Kwong Wah Hospital, Hospital Authority, Hong Kong

[8 ]Pamela Youde Nethersole Eastern Hospital, Hospital Authority, Hong Kong

[9 ]Tuen Mun Hospital, Hospital Authority, Hong Kong

[10 ]Princess Margaret Hospital, Hospital Authority, Hong Kong

[11 ]YY Kung Medical Centre, Hong Kong

[12 ]Joint Chinese University of Hong Kong-Beijing Genomics Institute Genome Research Centre, Hong Kong

[13 ]Beijing Genomics Institute at Shenzhen, Shenzhen, China

Author notes

Correspondence to: Y M D Lo loym@ 123456cuhk.edu.hk

Article

Publisher ID: chir807909

DOI: 10.1136/bmj.c7401

PMC ID: 3019239

PubMed ID: 21224326

SO-VID: 2e834925-c42f-43f2-9ccf-a3a7ae377b85

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This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study

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Most cited references 28

Long Term Outcomes Following Hospital Admission for Sepsis Using Relative Survival Analysis: A Prospective Cohort Study of 1,092 Patients with 5 Year Follow Up

Preparation of Artificial Plasma Membrane Mimicking Vesicles with Lipid Asymmetry

Outcomes in Patients with Acute and Stable Coronary Syndromes; Insights from the Prospective NOBORI-2 Study

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