Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing:Follow-up results of the TRIDENT-2 study

In the TRIDENT-2 study, all pregnant women in the Netherlands are offered genome-wide non-invasive prenatal testing (GW-NIPT) with a choice of receiving either full screening or screening solely for common trisomies. Previous data showed that GW-NIPT can reliably detect common trisomies in the general obstetric population and that this test can also detect other chromosomal abnormalities (additional findings). However, evidence regarding the clinical impact of screening for additional findings is lacking. Therefore, we present follow-up results of the TRIDENT-2 study to determine this clinical impact based on the laboratory and perinatal outcomes of cases with additional findings. Between April 2017 and April 2019, additional findings were detected in 402/110,739 pregnancies (0.36%). For 358 cases, the origin was proven to be either fetal (n = 79; 22.1%), (assumed) confined placental mosaicism (CPM) (n = 189; 52.8%), or maternal (n = 90; 25.1%). For the remaining 44 (10.9%), the origin of the aberration could not be determined. Most fetal chromosomal aberrations were pathogenic and associated with severe clinical phenotypes (61/79; 77.2%). For CPM cases, occurrence of pre-eclampsia (8.5% [16/189] vs 0.5% [754/159,924]; RR 18.5), and birth weigh

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Online cognition: factors facilitating reliable online neuropsychological test results

OBJECTIVE: Online neuropsychological test batteries could allow for large-scale cognitive data collection in clinical studies. However, the few online neuropsychological test batteries that are currently available often still require supervision or lack proper psychometric evaluation. In this paper, we have outlined prerequisites for proper development and use of online neuropsychological tests, with the focus on reliable measurement of cognitive function in an unmonitored setting. METHOD: First, we identified several technical, contextual, and psychological factors that should be taken into account in order to facilitate reliable test results of online tests in the unmonitored setting. Second, we outlined a methodology of quality assurance needed in order to obtain reliable cognitive data in the long run. RESULTS: Based on factors that distinguish the online unmonitored test setting from the traditional face-to-face setting, we provide a set of basic requirements and suggestions for optimal development and use of unmonitored online neuropsychological tests, including suggestions on acquiring reliability, validity, and norm scores. CONCLUSIONS: When properly addressing factors that could hamper reliable test results during development and use, online neuropsychological tests could aid large-scale data collection for clinical studies in the future. Investment in both proper development of online neuropsychological test platforms and the performance of accompanying psychometric studies is currently required

Reliability and validity of a self-administered tool for online neuropsychological testing: The Amsterdam Cognition Scan

Introduction: To facilitate large-scale assessment of a variety of cognitive abilities in clinical studies, we developed a self-administered online neuropsychological test battery: the Amsterdam Cognition Scan (ACS). The current studies evaluate in a group of adult cancer patients: test–retest reliability of the ACS and the influence of test setting (home or hospital), and the relationship between our online and a traditional test battery (concurrent validity). Method: Test–retest reliability was studied in 96 cancer patients (57 female; Mage = 51.8 years) who completed the ACS twice. Intraclass correlation coefficients (ICCs) were used to assess consistency over time. The test setting was counterbalanced between home and hospital; influence on test performance was assessed by repeated measures analyses of variance. Concurrent validity was studied in 201 cancer patients (112 female; Mage = 53.5 years) who completed both the online and an equivalent traditional neuropsychological test battery. Spearman or Pearson correlations were used to assess consistency between online and traditional tests. Results: ICCs of the online tests ranged from.29 to.76, with an ICC of.78 for the ACS total score. These correlations are generally comparable with the test–retest correlations of the traditional tests as reported in the literature. Correlating online and traditional test scores, we observed medium to large concurrent validity (r/ρ =.42 to.70; total score r =.78), except for a visuospatial memory test (ρ =.36). Correlations were affected—as expected—by design differences between online tests and their offline counterparts. Conclusions: Although development and optimization of the ACS is an ongoing process, and reliability can be optimized for several tests, our results indicate that it is a highly usable tool to obtain (online) measures of various cognitive abilities. The ACS is expected to facilitate efficient gathering of data on cognitive functioning in the near future

TRIDENT-2:National Implementation of Genome-Wide Non-Invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)—96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13—were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up