Cross-trimester repeated measures testing for Down's syndrome screening: an assessment.

OBJECTIVES: To provide estimates and confidence intervals for the performance (detection and false-positive rates) of screening for Down's syndrome using repeated measures of biochemical markers from first and second trimester maternal serum samples taken from the same woman. DESIGN: Stored serum on Down's syndrome cases and controls was used to provide independent test data for the assessment of screening performance of published risk algorithms and for the development and testing of new risk assessment algorithms. SETTING: 15 screening centres across the USA, and at the North York General Hospital, Toronto, Canada. PARTICIPANTS: 78 women with pregnancy affected by Down's syndrome and 390 matched unaffected controls, with maternal blood samples obtained at 11-13 and 15-18 weeks' gestation, and women who received integrated prenatal screening at North York General Hospital at two time intervals: between 1 December 1999 and 31 October 2003, and between 1 October 2006 and 23 November 2007. INTERVENTIONS: Repeated measurements (first and second trimester) of maternal serum levels of human chorionic gonadotrophin (hCG), unconjugated estriol (uE3) and pregnancy-associated plasma protein A (PAPP-A) together with alpha-fetoprotein (AFP) in the second trimester. MAIN OUTCOME MEASURES: Detection and false-positive rates for screening with a threshold risk of 1 in 200 at term, and the detection rate achieved for a false-positive rate of 2%. RESULTS: Published distributional models for Down's syndrome were inconsistent with the test data. When these test data were classified using these models, screening performance deteriorated substantially through the addition of repeated measures. This contradicts the very optimistic results obtained from predictive modelling of performance. Simplified distributional assumptions showed some evidence of benefit from the use of repeated measures of PAPP-A but not for repeated measures of uE3 or hCG. Each of the two test data sets was used to create new parameter estimates against which screening test performance was assessed using the other data set. The results were equivocal but there was evidence suggesting improvement in screening performance through the use of repeated measures of PAPP-A when the first trimester sample was collected before 13 weeks' gestation. A Bayesian analysis of the combined data from the two test data sets showed that adding a second trimester repeated measurement of PAPP-A to the base test increased detection rates and reduced false-positive rates. The benefit decreased with increasing gestational age at the time of the first sample. There was no evidence of any benefit from repeated measures of hCG or uE3. CONCLUSIONS: If realised, a reduction of 1% in false-positive rate with no loss in detection rate would give important benefits in terms of health service provision and the large number of invasive tests avoided. The Bayesian analysis, which shows evidence of benefit, is based on strong distributional assumptions and should not be regarded as confirmatory. The evidence of potential benefit suggests the need for a prospective study of repeated measurements of PAPP-A with samples from early in the first trimester. A formal clinical effectiveness and cost-effectiveness analysis should be undertaken. This study has shown that the established modelling methodology for assessing screening performance may be optimistically biased and should be interpreted with caution

MODELLING THE PREVALENCE OF DOWN SYNDROME WITH APPLICATIONS OF MARKOV CHAIN MONTE CARLO METHODS

This thesis was motivated by applications in the epidemiology of Down syndrome and prenatal screening for Down syndrome. Methodological problems arising in these applications include under-ascertainment of cases in livebirth studies, double-sampled data with missing observations and coarsening of data. These issues are considered from a classical perspective using maximum likelihood and from a Bayesian viewpoint employing Markov chain Monte Carlo (MCMC) techniques. Livebirth prevalence studies published in the literature used a variety of data collection methods and many are of uncertain completeness. In two of the nine studies an estimate of the level of under-reporting is available. We present a meta-analysis of these studies in which maternal age-related risks and the levels of under-ascertainment in individual studies are estimated simultaneously. A modified logistic model is used to describe the relationship between Down syndrome prevalence and maternal age. The model is then extended to include data from several studies of prevalence rates observed at times of chorionic villus sampling (CVS) and amniocentesis. New estimates for spontaneous loss rates between the times" of CVS, amniocentesis and live birth are presented. The classical analysis of live birth prevalence data is then compared with an MCMC analysis which allows prior information concerning ascertainment to be incorporated. This approach is particularly attractive since the double-sampled data structure includes missing observations. The MCMC algorithm, which uses single-component Metropolis-Hastings steps to simulate model parameters and missing data, is run under three alternative prior specifications. Several convergence diagnostics are also considered and compared. Finally, MCMC techniques are used to model the distribution of fetal nuchal translucency (NT), an ultrasound marker for Down syndrome. The data are a mixture of measurements rounded to whole millimetres and measurements more accurately recorded to one decimal place. An MCMC algorithm is applied to simulate the proportion of measurements rounded to whole millimetres and parameters to describe the distribution of NT in unaffected and Down syndrome pregnancies. Predictive probabilities of Down syndrome given NT and maternal age are then calculated

Two-stage approach for risk estimation of fetal trisomy 21 and other aneuploidies using computational intelligence systems

ObjectiveTo estimate the risk of fetal trisomy 21 (T21) and other chromosomal abnormalities (OCA) at 11-13weeks' gestation using computational intelligence classification methods. MethodsAs a first step, a training dataset consisting of 72054 euploid pregnancies, 295 cases of T21 and 305 cases of OCA was used to train an artificial neural network. Then, a two-stage approach was used for stratification of risk and diagnosis of cases of aneuploidy in the blind set. In Stage 1, using four markers, pregnancies in the blind set were classified into no risk and risk. No-risk pregnancies were not examined further, whereas the risk pregnancies were forwarded to Stage 2 for further examination. In Stage 2, using seven markers, pregnancies were classified into three types of risk, namely no risk, moderate risk and high risk. ResultsOf 36328 unknown to the system pregnancies (blind set), 17512 euploid, two T21 and 18 OCA were classified as no risk in Stage 1. The remaining 18796 cases were forwarded to Stage 2, of which 7895 euploid, two T21 and two OCA cases were classified as no risk, 10464 euploid, 83T21 and 61 OCA as moderate risk and 187 euploid, 50T21 and 52 OCA as high risk. The sensitivity and the specificity for T21 in Stage 2 were 97.1% and 99.5%, respectively, and the false-positive rate from Stage 1 to Stage 2 was reduced from 51.4% to approximate to 1%, assuming that the cell-free DNA test could identify all euploid and aneuploid cases. ConclusionWe propose a method for early diagnosis of chromosomal abnormalities that ensures that most T21 cases are classified as high risk at any stage. At the same time, the number of euploid cases subjected to invasive or cell-free DNA examinations was minimized through a routine procedure offered in two stages. Our method is minimally invasive and of relatively low cost, highly effective at T21 identification and it performs better than do other existing statistical methods. Copyright (c) 2017 ISUOG. Published by John Wiley & Sons Ltd

Non-invasive prenatal diagnostic test accuracy for fetal sex using cell-free DNA a review and meta-analysis

Background: Cell-free fetal DNA (cffDNA) can be detected in maternal blood during pregnancy, opening the possibility of early non-invasive prenatal diagnosis for a variety of genetic conditions. Since 1997, many studies have examined the accuracy of prenatal fetal sex determination using cffDNA, particularly for pregnancies at risk of an X-linked condition. Here we report a review and meta-analysis of the published literature to evaluate the use of cffDNA for prenatal determination (diagnosis) of fetal sex. We applied a sensitive search of multiple bibliographic databases including PubMed (MEDLINE), EMBASE, the Cochrane library and Web of Science. Results: Ninety studies, incorporating 9,965 pregnancies and 10,587 fetal sex results met our inclusion criteria. Overall mean sensitivity was 96.6% (95% credible interval 95.2% to 97.7%) and mean specificity was 98.9% (95% CI = 98.1% to 99.4%). These results vary very little with trimester or week of testing, indicating that the performance of the test is reliably high. Conclusions: Based on this review and meta-analysis we conclude that fetal sex can be determined with a high level of accuracy by analyzing cffDNA. Using cffDNA in prenatal diagnosis to replace or complement existing invasive methods can remove or reduce the risk of miscarriage. Future work should concentrate on the economic and ethical considerations of implementing an early non-invasive test for fetal sex

The prediction, diagnosis and management of complications in monochorionic twin pregnancies

Monochorionic twin pregnancies are high-risk and closely monitored antenatally. A systematic review revealed no existing predictive factors for twin-twin transfusion syndrome (TTTS), growth restriction, or intrauterine fetal death (IUFD). The Optimal Management of Monochorionic Twins (OMMIT) study found that first trimester inter-twin nuchal translucency discordance, crown-rump length discordance, β-hCG, PAPP-A, AFP, PlGF and sFlt-1 do not predict adverse outcome. A difference was seen in novel second trimester biomarkers: in the recipient twin amniotic fluid metabolites pre- and post-fetoscopic laser ablation; and a relationship with recipient twin cardiac function was demonstrated. Discovery work on miRNA in second trimester maternal serum of TTTS pregnancies found no difference compared to uncomplicated monochorionic twin pregnancies. A systematic review provided a more personalised risk prediction for the surviving co-twin in single IUFD, including that that the rate of abnormal brain imaging is 20% and the IUFDs occurring at 14-28 weeks are at higher risk. A preliminary study of parent-fetal antenatal and postnatal attachment and depression in TTTS pregnancies found maternal attachment increased postnatally and depressive symptoms decreased, whereas paternal scores did not change. This thesis has reported exciting findings which have clinical implications, and advance knowledge of complicated monochorionic twin pregnancies

Cell-free DNA-based noninvasive prenatal screening for Down syndrome in the Quebec healthcare system : health economic aspects

Introduction: Au Québec, environ 110 000 femmes enceintes sont éligibles au dépistage prénatal volontaire de la trisomie 21(T21). Différentes stratégies de dépistage sélectionnent environ 4% des femmes à haut risque pour le test invasif (amniocentèse) en vue d'un diagnostic définitif. Les nouveaux tests génomiques prénataux non invasifs (TGPNI) utilisant l'ADN fœtal circulant dans le sang maternel pourraient réduire ces procédures invasives. Leur introduction dans les programmes nationaux de dépistage requiert cependant que des données sur leur coût-efficacité et leur impact budgétaire soient produites. Objectifs : L’objectif principal de cette thèse était d'évaluer les aspects économiques attendus de l'introduction du TGNI dans le programme québécois de dépistage de la trisomie 21. La première étude a consisté en une revue systématique de la littérature des évaluations économiques sur les TGPNI. La deuxième étude a porté sur l'évaluation économique de 7 stratégies de dépistages incluant le TGPNI comparées ainsi que des 6 stratégies de dépistage traditionnelles recommandées par la Société canadienne d’obstétrique et de gynécologie(SOGC). La troisième étude a porté sur l'évaluation de l'impact budgétaire attendu de l’implantation du dépistage par TGPNI dans le programme québécois de dépistage de la trisomie 21. Méthodologie: Une revue systématique de la littérature a été réalisée pour la première étude. Pour la deuxième étude, ainsi que la troisième, des modèles de décision semi-markoviens ont été élaborés pour simuler l’évaluation économique et l'impact budgétaire du dépistage par TGPNI pour une cohorte virtuelle de femmes enceintes similaire à celle des femmes enceintes du Québec en termes d'âge et de nombre de grossesses par âge. La perspective du système de santé québécois a été considérée. Pour l’évaluation économique, 13 stratégies de dépistage ont été comparées : 6 traditionnelles recommandées par la Société canadienne d’obstétrique et de gynécologie, 6 incluant le TGPNI comme test de dépistage de deuxième intention et 1 considérant le TGPNI en première intention. Quant à l’analyse d’impact budgétaire, elle a porté sur l’option considérée comme la plus coût-efficace par la deuxième étude, c’est-à-dire le TGPNI en deuxième intention offert aux femmes à haut risque (Sérum intégré +TGPNI). Cette option a été comparée à la stratégie actuellement offerte par le programme de dépistage au Québec (Sérum intégré). La principale issue pour l'analyse coût-efficacité était le coût additionnel par trisomie 21 additionnelle détectée. Celle de l'analyse d'impact budgétaire était la différence de coûts entre la stratégie incluant le TGPNI et la stratégie de dépistage actuelle. Résultats: La première étude qui a inclus 16 études a révélé que par rapport aux stratégies de dépistage actuelles, la stratégie offrant le TGPNI à toutes les femmes n'était pas coût-efficace. C'est l'option du TGPNI offert aux femmes enceintes à risque élevé qui s'avère l'option la plus coût-efficace dans la majorité des études incluses. La deuxième étude a montré que, sur un total de 13 stratégies comparées, la stratégie « Dépistage par sérum intégré suivie par le TGPNI » est celle qui coûte le moins cher et la stratégie « TGPNI universel » est celle qui coûte le plus bien qu'étant la plus efficace. Ainsi, la stratégie « Dépistage par sérum intégré suivie par le TGPNI » est considérée comme plus la coût-efficace. D'autres stratégies, bien que relativement plus efficace pour détecter le nombre de cas T21, entraînent une augmentation des coûts marginaux par cas additionnel détecté allant de 61 623 $à 1 553 615$. Les résultats étaient sensibles au coût du TGPNI et aux seuils considérés pour déterminer les femmes enceintes à risque élevé. La troisième étude a montré que le TGPNI offert aux femmes à haut risque identifiées par le programme de dépistage actuel serait abordable pour le système de santé québécois. Comparativement au programme de dépistage actuel, son implantation se ferait à coût neutre considérant une modeste économie annuelle de 80 432 $(IC à 95$ - 81 462 $). Les résultats étaient sensibles aux coûts du TGPNI et au taux d'acceptation des tests diagnostiques invasifs. Conclusion: Le TGPNI comme test de seconde intension, c'est-à-dire offert aux femmes à haut risque selon les critères du programme de dépistage actuel, est coût-efficace et abordable pour le système de santé québécois. Avant d'envisager son introduction, les décideurs devraient cependant considérer d'autres aspects, notamment les aspects éthiques.Introduction: In the Province of Quebec, about 110,000 pregnant women are eligible to voluntary prenatal screening for trisomy 21(T21). Conventional screening strategies select about 4$ 61,623 to $1,553,615). Results were sensitive to NIPT cost and cut-offs considered to determine high risk pregnant women. The third study found that NIPT as a second-tier test offered to high-risk women identified by the current screening program is affordable for the Quebec health care system. Compared to the current screening program, this strategy could be implemented at a neutral cost considering a modest yearly saving of$80,432 (95% CI: $79,874-$81,462). Results were sensitive to the NIPT costs and the uptake-rate of invasive diagnostic tests. Conclusion: NIPT as a second-tier test offered to high-risk women identified by the current screening program is cost-effective and affordable for the Quebec health care system. Decision makers should consider its introduction after considerations of others aspects such as ethical issues

Summaries of plenary, symposia, and oral sessions at the XXII World Congress of Psychiatric Genetics, Copenhagen, Denmark, 12-16 October 2014

The XXII World Congress of Psychiatric Genetics, sponsored by the International Society of Psychiatric Genetics, took place in Copenhagen, Denmark, on 12-16 October 2014. A total of 883 participants gathered to discuss the latest findings in the field. The following report was written by student and postdoctoral attendees. Each was assigned one or more sessions as a rapporteur. This manuscript represents topics covered in most, but not all of the oral presentations during the conference, and contains some of the major notable new findings reported

A description of the methods of the Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be (nuMoM2b)

OBJECTIVE: The primary aim of the "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" is to determine maternal characteristics, which include genetic, physiologic response to pregnancy, and environmental factors that predict adverse pregnancy outcomes. STUDY DESIGN: Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at 3 study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine, cervicovaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending at <37+0 weeks' gestation. Key study hypotheses involve adverse pregnancy outcomes of spontaneous preterm birth, preeclampsia, and fetal growth restriction. RESULTS: We recruited 10,037 women to the study. Basic characteristics of the cohort at screening are reported. CONCLUSION: The "Nulliparous Pregnancy Outcomes Study: monitoring mothers-to-be" cohort study methods and procedures can help investigators when they plan future projects