Eric L. Krivchenia

MOMs (multiples of the median) and DADs (disciminant aneuploidy detection): Improved specificity and cost-effectiveness of biochemial screening for aneuploidy with DADs☆

OBJECTIVEnOur purpose was to assess the efficacy of double- and triple-screening paradigms for Down syndrome and to develop a more logical, statistical approach to risk prediction that will decrease the cost of screening and allow the incorporation of new parameters appropriately weighted for their contribution.nnnSTUDY DESIGNnData from 24,504 patients who had biochemical screening for Down syndrome by single (alpha-fetoprotein), double (alpha-fetoprotein, beta-human chorionic gonadotropin), or triple screening (alpha-fetoprotein, beta-human chorionic gonadotropin, unconjugated estriol) who had complete outcome information were analyzed by (1) existing gaussian-based methods, (2) the Glasgow ratio method, and (3) a new statistical approach (i.e., directly adjusted data sets for discriminant aneuploidy detection [DADs])nnnRESULTSnBy use of individual risk-based thresholds for at risk status, both double and triple screening performed far better than single screening, but the percentages of patients at risk varied widely. When the percentages at risk were held constant, the sensitivity of double and triple screenings was similar, suggesting that there are no benefits of using estriol as a third marker. For 25,000 patients the use of only alpha-fetoprotein and beta-human chorionic gonadotropin would save about

Aneuploidy with Neural Tube Defects: Another Reason for Complete Evaluation in Patients with Suspected Ultrasound Anomalies or Elevated Maternal Serum Alpha-Fetoprotein

500,000, with no decrease in sensitivity. With the DADs approach a statistically sound model giving more stable estimates was developed that permits each factor to be analyzed for its own explained proportion of variance and allows each parameter to have different weighting. For this data set the same sensitivity was seen with, conservatively, a 1% reduction in the percentage of patients at risk, which would reduce by 250 the number of amniocenteses, at a further savings of about

Integration of genetics and ultrasonography in prenatal diagnosis: Just looking is not enough

400,000.nnnCONCLUSIONSnBy use of existing methods, double screening is equally as effective as triple screening, so that the expense of estriol is unnecessary. The DADs approach, by allowing for variable weighting of parameters, lowers the at risk percentage and will permit a much more flexible approach as new parameters become available. Changing to DADs and eliminating estriol should achieve higher specificity for the same sensitivity and save, conservatively, about

Similarity of insulin-dependent diabetics' and non-insulin-dependent diabetics' levels of beta-hCG and unconjugated estriol with controls: no need to adjust as with alpha-fetoprotein.

900,000 in this series. Extrapolated nationally, if confirmed, the annual savings could approach

Logistic regression generated probability estimates for trisomy 21 outcomes from serum alpha fetoprotein and beta human chorionic gonadotrophin: Simplification with increased specificity

72,000,000.

An Automated Image Analysis Method for the Measurement of Neutrophil Alkaline Phosphatase in the Prenatal Screening of Down Syndrome

Some recent reports have suggested that invasive testing is unnecessary when ultrasound either confirms or refutes a neural tube defect (NTD). However, counseling for recurrence risks and the possibilities for in utero therapy would be significantly altered by an aneuploid karyotype. We report our experience with 53 pregnancies affected by NTD in which we found 13.2% of these fetuses with abnormal chromosomes. In view of the higher than previously published incidence of aneuploidy, we believe that fetal karyotypes are essential in the evaluation of all fetuses with NTDs.

Principles of screening.

OBJECTIVEnThere has been a gradual shift of the focus of prenatal diagnosis from genetics to ultrasonography. We assessed our primary genetics approach to determine what would be missed without the genetics component.nnnSTUDY DESIGNnWe evaluated referral indications for patients with normal and abnormal prenatal findings from Jan. 1, 1990, to March 31, 1995, and categorized them according to type of fetal anomalies and genetic abnormalities found. Discordance among initial indication, identified risk factors, and observed abnormalities was assessed.nnnRESULTSnThe proportion of patients referred for very-high-risk indications increased over time; 13.5% of all patients (1992 of 14,725) had abnormalities. Abnormal outcomes were categorized as 26% chromosomal, 58% ultrasonographic dysmorphologic features, 11% biochemical or deoxyribonucleic acid disorders, 5% infectious, and 11% other. Of the cases of ultrasonographic dysmorphism (exclusive of the aneuploidies), 3.5% were ultimately determined to be syndromic and 2.5% to be discrepant, that is, having a different abnormality than the referred diagnosis. Including the whole spectrum of disorders seen, half of the abnormalities would not be detectable with even high-quality ultrasonography.nnnCONCLUSIONnA large number of abnormal findings were not consistent with initial indication for referral. Correct diagnosis depended on increased acuity provided by genetic pedigree analysis and recognition of syndromes. Diligence in the search for associated anomalies, aneuploidy, pedigree analysis, and syndromic abnormalities remain critical components in the differential diagnosis. The elucidation of unexpected findings suggests the advantages of early counseling and a genetics-based approach combined with tertiary rather than primary ultrasonography with counseling only when anomalies are detected.

Precise gaussian distribution functions of maternal serum α-fetoprotein and free β-subunit of human chorionic gonadotropin for trisomy 21 screening: Improved accuracy for patient counseling

Objective: To determine if the same systematic alteration of serum values seen for alpha-fetoprotein (AFP) in diabetic patients is also seen for β-hCG and unconjugated estriol (uE3). Methods: Serum AFP, β-hCG, and uE3 results were obtained in 18,639 patients for whom complete follow-up information was obtained. Patients were divided into euglycemic (n = 18,088), insulin-requiring diabetics (n = 104), and non-insulin-requiring diabetics (n = 437), as well as by race. Results: The 20% adjustment used for AFP appropriately corrects serum values. No such systematic variation is seen for either β-hCG or uE3 by glycemic status or race. Conclusion: No adjustment for β-hCG or uE3 is necessary for diabetes for biochemical screening programs.

Correction for insulin-dependent diabetes in maternal serum ⍺-fetoprotein testing has outlived its usefulness

Traditional Gaussian approaches to biochemical screening make calculations very cumbersome. We have sought to develop a logistic regression mathematical model for the calculation of risk for trisomy 21 in multiple marker screening that would be more user friendly. Biochemical screening data from 15,444 patients with confirmed normal outcomes and 28 with trisomy 21 were analyzed by logistic regression analysis (LRA) to produce a direct mathematical approach to risk calculation that combines the improvements in sensitivity and specificity already demonstrated by us with extreme value cumulative function surface fittings, but which can be extended for other exploratory variables. LRA yields a 71.4% sensitivity with a 95% specificity which is comparable to our previously published discriminant aneuploidy detection (DADs) approach; both are an improvement over the commonly used Gaussian approach of risk assessment. In our study population, LRA performed as well as DADs; both performed better than the Gaussian method, and LRA is a simpler approach.

Procedural risks versus theology: Chorionic villus sampling for Orthodox Jews at less than 8 weeks' gestation

OBJECTIVESn(1) To develop an image analysis method for the measurement of neutrophil alkaline phosphatase (NAP); (2) To establish a correlation of urea-resistant fraction of NAP (URNAP)/NAP scoring between the manual and automated methods, and (3) to assess the value of URNAP/NAP in the prenatal screening of Down syndrome.nnnSTUDY DESIGNnSlides from 15 unaffected controls were blindly scored by both methods. The Pearson test was used for correlation analysis. Slides from 15 Down syndrome pregnancies and 25 unaffected controls were scored manually.nnnRESULTSnA coefficient r = 0.93 was obtained comparing the URNAP/NAP scores generated by the two methods. Average time for scoring by the automated method was 8 min. The median URNAP/NAP values for Down syndrome and unaffected controls were 112/86.1 and 51/51.5, respectively.nnnCONCLUSIONSnScores obtained by both methods highly correlate. Automated scoring is threefold faster. Down syndrome cases have higher URNAP/NAP scores compared to unaffected controls, which suggests that URNAP/NAP is an extremely useful marker for mid-trimester prenatal screening.