Three-stage contingent screening for Down syndrome.

OBJECTIVE: To demonstrate the potential value of three-stage sequential screening for Down syndrome. METHODS: Protocols were considered in which maternal serum pregnancy associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (hCG) measurements were taken on all women in the first trimester. Those women with very low Down syndrome risks were screened negative at that stage and nuchal translucency (NT) was measured on the remainder and the risk reassessed. Those with very low risk were then screened negative and those with very high risk were offered early diagnostic testing. Those with intermediate risks received second-trimester maternal serum alpha-fetoprotein, free beta-hCG, unconjugated estriol and inhibin-A. Risk was then reassessed and those with high risk were offered diagnosis. Detection rates and false-positive rates were estimated by multivariate Gaussian modelling using Monte-Carlo simulation. RESULTS: The modelling suggests that, with full adherence to a three-stage policy, overall detection rates of nearly 90% and false-positive rates below 2.0% can be achieved. Approximately two-thirds of pregnancies are screened on the basis of first-trimester biochemistry alone, five out of six women complete their screening in the first trimester, and the first-trimester detection rate is over 60%. CONCLUSION: Three-stage contingent sequential screening is potentially highly effective for Down syndrome screening. The acceptability of this protocol and its performance in practice, should be tested in prospective studies.

Evaluation of Cystatin C as a marker of renal injury following on-pump and off-pump coronary surgery.

OBJECTIVE: Cardiopulmonary bypass is regarded as an important contributor to renal injury, whereas off-pump surgery is considered less damaging. Cystatin C, a cystine protease inhibitor, is more sensitive and specific than creatinine in the assessment of renal function. We assessed the value of Cystatin C in quantifying clinical and subclinical renal injury following on-pump and off-pump cardiac surgery. METHODS: Sixty consecutive patients were recruited: 30 patients undergoing on-pump CABG and 30 patients undergoing off-pump CABG. Blood samples were collected pre-operatively and on days 1, 2 and 4 postoperatively to measure serum creatinine and serum Cystatin C. Urinary samples were collected concurrently to measure microalbumin and N-acetyl-beta-glucosaminidase, denoting changes in renal glomerular and tubular function respectively. RESULTS: The off-pump group were older (65+/-11 vs. 61+/-8 years; P=0.046), had a higher mean Parsonnet score (9.4+/-6.2 vs. 5.4+/-3.6, P<0.01) and received fewer grafts (2.4+/-0.9 vs. 3.1+/-0.7; P<0.01) compared to the on-pump group. The groups were otherwise matched with respect to preoperative renal function and left ventricular function. Patients undergoing on-pump CABG had greater increases in all four parameters of renal injury. Adjustment for preoperative differences increased the size and significance of the effect of off-pump vs. on-pump surgery (percent difference 13%; 95% CI 2-26 for creatinine, and 16%; 95% CI 4-29 for Cystatin C). Cystatin and creatinine were strongly correlated with each other. CONCLUSIONS: Avoidance of cardiopulmonary bypass may reduce renal injury particularly in higher risk patients. Cystatin C proved to be a simple and sensitive measure of overall renal function and can be used in the routine assessment of renoprotective strategies.

Age-standardisation when target setting and auditing performance of Down syndrome screening programmes.

OBJECTIVE: To describe and illustrate a method of setting Down syndrome screening targets and auditing performance that allows for differences in the maternal age distribution. METHODS: A reference population was determined from a Gaussian model of maternal age. Target detection and false-positive rates were determined by standard statistical modelling techniques, except that the reference population rather than an observed population was used. Second-trimester marker parameters were obtained for Down syndrome from a large meta-analysis, and for unaffected pregnancies from the combined results of more than 600,000 screens in five centres. Audited detection and false-positive rates were the weighted average of the rates in five broad age groups corrected for viability bias. Weights were based on the age distributions in the reference population. RESULTS: Maternal age was found to approximate reasonably well to a Gaussian distribution with mean 27 years and standard deviation 5.5 years. Depending on marker combination, the target detection rates were 59 to 64% and false-positive rate 4.2 to 5.4% for a 1 in 250 term cut-off; 65 to 68% and 6.1 to 7.3% for 1 in 270 at mid-trimester. Among the five centres, the audited detection rate ranged from 7% below target to 10% above target, with audited false-positive rates better than the target by 0.3 to 1.5%. CONCLUSION: Age-standardisation should help to improve screening quality by allowing for intrinsic differences between programmes, so that valid comparisons can be made.