Prenatal maternal plasma DNA screening for cystic fibrosis: A computer modelling study of screening performance.

Background: Prenatal cystic fibrosis (CF) screening is currently based on determining the carrier status of both parents. We propose a new method based only on the analysis of DNA in maternal plasma. Methods: The method relies on the quantitative amplification of the CF gene to determine the percentage of DNA fragments in maternal plasma at targeted CF mutation sites that carry a CF mutation. Computer modelling was carried out to estimate the distributions of these percentages in pregnancies with and without a fetus affected with CF. This was done according to the number of DNA fragments counted and fetal fraction, using the 23 CF mutations recommended by the American College of Medical Genetics for parental carrier testing. Results: The estimated detection rate (sensitivity) is 70% (100% of those detected using the 23 mutations), the false-positive rate 0.002%, and the odds of being affected given a positive screening result 14:1, compared with 70%, 0.12%, and 1:3, respectively, with current prenatal screening based on parental carrier testing. Conclusions: Compared with current screening practice based on parental carrier testing, the proposed method would substantially reduce the number of invasive diagnostic procedures (amniocentesis or chorionic villus sampling) without reducing the CF detection rate. The expected advantages of the proposed method justify carrying out the necessary test development for use in a clinical validation study.The author(s) declared that no grants were involved in supporting this work

THE TESTIS AND REPRODUCTION IN MALE NECTURUS, WITH EMPHASIS ON NECTURUS-LEWISI (BRIMLEY)

Volume: 10Start Page: 53End Page: 7

Mechanism of increased maternal serum total activin A and inhibin A in preeclampsia

OBJECTIVE: To determine whether increased levels of maternal serum total activin A and inhibin A in preeclampsia are related to total blood volume, urinary clearance, or placental production. STUDY DESIGN: Activin A and inhibin A levels were measured in preeclamptic subjects and matched normotensive gravidas. In a subset of preeclamptic subjects (n = 21) and controls (n = 30), we performed blood volume studies. In an overlapping subset of preeclamptic subjects (n = 56), creatinine clearance results were available. Placental tissue was obtained from six preeclamptics and matched normotensive gravida for analysis of activin A and inhibin A mRNA expression. RESULTS: Maternal serum levels of inhibin A but not activin A were significantly negatively correlated with blood volume in preeclampsia (r(2) =.26, P =.017, and r(2) =.02, P =.44, respectively). Levels of both proteins were negatively correlated to creatinine clearance (r(2) =.29, P <.0001, and r(2) =.15, P =.003, respectively). Placental mRNA expression for both the alpha and betaA subunits was increased in preeclampsia (P =.038 and.049, respectively). CONCLUSION: Although placental mRNA expression of the subunits for both analytes is increased in preeclampsia, the increased levels of activin A appear to be more specifically a reflection of increased placental production than do the increased levels of inhibin A

Comparison of 12 assays for detecting hCG and related molecules in urine samples from Down syndrome pregnancies.

Urine is a new medium for Down syndrome testing. In an effort to determine the best type of human chorionic gonadotropin (hCG)-related immunoassay for urine testing, we examined 14 Down syndrome and 91 unaffected pregnancy urine samples with 12 established assays. The assays included (a) those that detect hCG beta-core fragment only; (b) those that detect beta-core fragment with less than 18 per cent free beta-subunit cross-reactivity; (c) that which equally detects free beta-subunit and beta-core fragment; and (d) those that detect hCG, free beta-subunit, or combinations thereof. The seven type a and b assays had the highest sensitivity for Down syndrome. The median MOM for Down syndrome was 5·93 (range 4·73-7·53). At a 10 per cent false-positive rate, the median observed detection rate was 93 per cent (range 79-100 per cent) and the median predicted detection rate was 85 per cent (range 69-96 per cent). The assays that did not mainly detect beta-core fragment (types c and d) had poorer screening performance. The median MOM for Down syndrome was 2·70 (range 2·16-3·63 MOM). At a 10 per cent false-positive rate, the median observed detection rate was 50 per cent (range 36-64 per cent) and the median predicted detection rate was 37 per cent (range 21-62 per cent). We infer that the assays that only detect beta-core fragment, or beta-core fragment with minor free beta-subunit cross-reactivity (types a and b), are the better urine-based tests for Down syndrome screening