Calculation Of Patient-specific Risk Research Articles

The impact of bias in MoM values on patient risk and screening performance for Down syndrome

First and second trimester screening protocols for Down syndrome rely on marker values being referred to smoothed median values to produce adjusted multiple of the median (MoM) values to standardise for factors such as assay, gestation, maternal weight, smoking status, and so on. Changes in assay components, such as reagent lot, and inappropriate use of published regression equations for smoothed medians have resulted in biases in reported MoM values that in many applications remain uncorrected. This paper investigates the impact of these biases on patient-specific risk estimates and screening performance, and concludes that a 10% bias for an individual marker can result in an increase of between 1 and 2% in the false positive rate of the programme. A simple formula is also derived that enables the impact of these biases to be determined without the need for simulation, thus making it easier to design effective statistical quality control procedures to monitor the output of screening software algorithms. To determine the impact of bias in MoM values on detection rates, false positive rates and patient-specific risks for Down syndrome. We show that bias in MoM values affects risk through a multiplicative factor, and present an approximation to estimate this factor. We then show how bias in MoM values changes the effective risk threshold in the screening test, and hence the test's performance characteristics are determined by reference to a different point on the ROC curve for that test. Our approximation is based on the assumption of equal variance covariance structure for the unaffected and T21 log MoM values. We demonstrate, using computer simulation and supportive theoretical results, that the approximation is reliable in situations encountered in practice. Applications of the approximation are also discussed in respect of establishing effective quality control rules for median MoMs. Substantial changes in patient risk estimates and overall screening performance can result from the sort of biases in marker MoM values encountered in routine practice. In particular, biases of 10% in individual median marker MoM values can produce a four-fold range of risks when using the triple test. A 10% bias in a single marker will change the false positive rates by up to 2%. The effects on the false positive rate are approximately additive and, in cases where all markers are biased towards Down syndrome, biases in all three markers for the triple test can more than double the false positive rate. Biases in marker MoM values can occur in many ways, inappropriate median values, kit lot change, drift in assay performance and operator effects. We present methods which allow the impact of these changes to be assessed in relation to patient-specific risks and the overall screening performance. This, in turn, will enable appropriate quality control procedures to be established to control the magnitude of reported marker MoM biases, or equivalently, the magnitude of biases associated with the calculation of patient-specific risks.

Uterine artery Doppler screening for adverse pregnancy outcome

This article reviews publications in the area of uterine artery Doppler screening that were published during the past year. Studies have shown that assessment of a woman's level of risk for pre-eclampsia by uterine artery Doppler performs better than maternal history alone. Combination of maternal history and uterine artery Doppler findings leads to even more accurate assessment of risk, and allows calculation of patient-specific risk. Combining screening with uterine artery Doppler and maternal serum biochemical markers has been explored in some studies, but data remain limited and larger prospective longitudinal studies are needed to asses the effectiveness of these techniques. A number of promising markers for development of the disease have been identified, however, including pregnancy associated plasma protein-A, inhibin-A, activin-A and fibronectin, as well as placental growth factor, vascular endothelial growth factor and soluble fms-like tyrosine kinase 1. Uterine artery Doppler has proved useful in identifying women at high and low risk for developing complications of uteroplacental insufficiency and may aid in stratifying antenatal care. In addition, it can identify women in whom biochemical markers should be measured in order to develop screening tests and aid in evaluation of the pathophysiology of impaired placentation and pre-eclampsia. Whether pharmacological intervention in women identified to be at high risk for pre-eclampsia on the basis of Doppler is effective in reducing the incidence of the disease remains to be established.

The effects of gestation dating on the calculation of patient-specific risks in Down's syndrome screening: multivariate case.

When screening for Down's syndrome using biochemical markers, the measurements are adjusted for the gestational age of the fetus because the concentrations of the markers are known to change with gestational age. This adjustment is performed by referring each marker measurement to the population median for that marker for the appropriate estimated gestational age group. The measurement of gestational age is subject to error, whichever method is used, and so the population median used is usually the median of a mixture of distributions for different true gestational ages. Most screening programmes aim for a specific number of weeks and this produces a concentrated distribution of true gestational ages. This fact, combined with dating errors, leads to an asymmetric mixture for each gestational age group and hence to bias in the estimates of the medians. In a previous communication we have shown how the proportions in this mixture distribution can be estimated and how the true medians corresponding to a true gestational age can be estimated. The calculations presented were performed using a single marker, and the details of our method were restricted to this situation. This paper extends the method to the multimarker situation and, as expected, leads to a gain in the detection rate for a specified false positive rate. The true patient-specific risk estimates are again markedly different from the quoted nominal value obtained by ignoring the dating errors. The data set on which the method is illustrated uses two markers, although the technique generalises in an obvious way to more than two.

The effects of gestation dating on the calculation of patient specific risks in Down's syndrome screening.

In Down's syndrome screening using biochemical markers, the marker concentrations are adjusted for the gestational age of the fetus, since they are known to change with gestational age. This adjustment is performed by referring to the population median of each marker for the appropriate gestational age group. The measurement of gestational age is subject to error, whatever method is used, and the population median used is actually the median of a mixture of distributions for different true gestational ages. We show how the proportions in this mixture can be estimated and how the true median corresponding to a given true gestational age can be estimated. For simplicity, we consider the case of using a single marker, namely maternal serum alpha-fetoprotein, and show that the usual estimation method has considerable bias. The effect of this mixture on the calculation of patient-specific risks is discussed and we show that detection rates can be improved by allowing for this error in the dating process. The overall detection rate is increased by about 1%. The increase in detection rate is age-dependent and for some maternal ages the increase is of the order of 5%. The comparative effects of different methods for dating are discussed.