The perception of facial asymmetry using 3-dimensional simulated images.

OBJECTIVE: To investigate the perception of facial asymmetry in young adults to identify the amounts of chin asymmetry that can be regarded as normal and may benefit from correction. MATERIALS AND METHODS: Three-dimensional (3D) images of 56 individuals of mixed ethnicity were obtained and used to produce average 3D images of male and female faces. Distortion was then applied to these average faces using a 3D graphics package to simulate different amounts of chin point asymmetry. Five observer groups (lay individuals, dental students, dental care professionals, dental practitioners, and orthodontists) assessed timed presentations of 3D images, rating them as "normal," "acceptable," or "would benefit from correction." Time-to-event analysis was used to assess the level of chin asymmetry perceived as normal and beneficial for correction for each group. RESULTS: The factors influencing the perception of facial asymmetry were the degree of asymmetry and the observer group. Direction of the asymmetry and gender of the assessed individual did not affect the perception of asymmetry, except in the 4- to 6-mm distortion range. The gender of the observer had no influence on perception. There were statistically significant differences in the amounts of asymmetry that the laypeople and orthodontists considered to be normal (5.6 ± 2.7 mm and 3.6 ± 1.5 mm, respectively; P < .001) and felt would benefit from surgical correction (11.8 ± 4.0 mm and 9.7 ± 3.0 mm, respectively; P  =  .001). CONCLUSIONS: Perception of asymmetry is affected by the amount of asymmetry and the observer group, with orthodontists being more critical.

Interference in the autoDELFIA(R) hAFP immunoassay and effect on second-trimester Down's syndrome screening.

BACKGROUND: Falsely decreased serum alphafetoprotein (AFP) concentrations are reported in the autoDELFIA(®) hAFP immunoassay due to interference by complement. AFP is measured, using this assay, as part of second-trimester and integrated Down's syndrome screening tests. Decreased AFP concentrations increase the calculated risk of Down's syndrome; therefore falsely low AFP, due to assay interference, may artificially increase a patient's risk, and have the potential to cause false screen positive results. It was our aim to assess whether negative interference in the autoDELFIA(®) hAFP assay was a cause of very low AFP concentrations, and to examine the effect of falsely decreased concentrations on the calculated risk of Down's syndrome. METHODS: Three hundred and twenty-three sequential Down's screening serum samples with very low serum AFP concentration (<15 KU/L) using the autoDELFIA(®) hAFP immunoassay were selected and AFP re-measured using the E170 AFP immunoassay. RESULTS: Interference was detected in nine samples (from eight patients) on the basis of discordant AFP concentrations. The interference decreased following storage of samples at 4°C to deplete complement. Use of the falsely low AFP concentrations to calculate risk of Down's syndrome resulted in significantly increased calculated risk compared with complement depleted results. CONCLUSIONS: Laboratories should be aware that falsely low AFP concentrations due to complement interference may be obtained using the autoDELFIA(®) hAFP immunoassay. We have shown that falsely low AFP concentrations increase the calculated risk of Down's syndrome. This is a potential cause of false Down's syndrome screen positive results.

Neonatal plasma TSH--estimated upper reference intervals for diagnosis and follow up of congenital hypothyroidism.

Age- and method-dependent plasma TSH reference intervals are essential for the diagnosis and management of congenital hypothyroidism. However, accurate reference intervals for plasma TSH have not been adequately defined due to the difficulties in obtaining samples from a healthy paediatric population. To overcome the difficulties in generating such intervals we estimated method-dependent plasma TSH upper-reference intervals by determining the blood spot TSH upper-reference interval from newborn blood spot TSH screening data (N = 10,697) and then derived method-dependent conversion factors for blood spot TSH to plasma TSH concentration from paired-blood spot and plasma TSH measurements. The upper reference interval for blood spot TSH of 3.04 mU/L was obtained from the 97.5th centile of the selected data. Using experimentally-derived conversion factors, estimates of plasma TSH upper reference intervals of 7.6, 6.3, 7.3, 8.3 and 6.5 mU/L were obtained for the Siemens Centaur, Abbott Architect, Roche Elecsys E170, Siemens Immulite 2000 and Beckman access HYPERsensitive TSH assays respectively. These estimated method-dependent plasma TSH upper reference intervals will be of great practical use to clinicians to diagnose and to follow up infants found to have increased blood spot TSH concentrations identified by Newborn Screening programmes.

A test of association between spatially defined exposure patterns and health outcome risk contours.

Advances in the availability of geographically referenced health and environmental quality data of high spatial resolution have created new opportunities in environmental epidemiology. Novel statistical methods for linking health, exposure, and hazards are required to underpin the development of public health tracking. A test for the association between spatial contours of health risk and exposure is outlined. This test is examined using, as an example, the spatial contours of congenital malformation risk obtained from a routine dataset in the vicinity of a landfill site and an exposure model based on exponential reduction with distance from the site. Spatial contours of risk of congenital malformation were simulated using the exposure model stated and a given population pattern. These were compared with the corresponding expected risk derived from routine birth data to yield relative risk contours. For each simulation three test statistics were devised: the slope of the regression line of standardized relative risk on exposure level, the proportion of standardized relative risks above zero, and the mean standardized relative risk of individuals not subject to exposure. The distributions of these test statistics (under the null no exposure from site and alternative hypotheses) were determined from a simulation exercise. A comparison of receiver operator characteristic (ROC) curves between those relating to the proposed test and those relating to a widely used method proposed by Stone (1988) demonstrated our test to be more efficient. Formal statistical testing of the concordance between spatial contours of risk and environmental exposure enables optimal use of spatial data.

First trimester screening for Down syndrome using free beta hCG, total hCG and PAPP-A: an exploratory study.

OBJECTIVE: To investigate the potential utility of first trimester screening for Down syndrome using Free beta-hCG, total hCG and PAPP-A. MATERIALS AND METHODS: Using estimates from the literature, a simulation study was undertaken to estimate the performance of tests incorporating, Free beta-hCG, total hCG and PAPP-A at gestations of 8-12 weeks. We used sensitivity analysis to assess the effect of departures from the assumed model. RESULTS: We estimate that detection rates in excess of 75% for a false positive rate (FPR) of 3% can be achieved with first trimester measures of PAPP-A, total hCG and Free beta-hCG at 8 weeks-the addition of total hCG adding 11%. Detection rates of around 90% for a FPR of 3% can be achieved through the inclusion of nuchal translucency (NT) at 12 weeks to these early first trimester biochemical markers. Our analysis indicates that the marginal benefit of adding total hCG diminishes rapidly with gestational age and that there is little benefit from adding total hCG later than 10 weeks of gestation. CONCLUSION: The performance of first trimester screening using early combinations of total hCG, Free beta-hCG and PAPP-A should be assessed in further studies.

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

UNLABELLED: 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. OBJECTIVE: To determine the impact of bias in MoM values on detection rates, false positive rates and patient-specific risks for Down syndrome. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Sonographic screening for trisomy 13 at 11 to 13(+6) weeks of gestation.

OBJECTIVE: The purpose of this study was to examine the sonographic features of trisomy 13 at 11 to 13(+6) weeks of gestation. STUDY DESIGN: This was a retrospective study that examined the features of trisomy 13 at the ultrasound scan at 11 to 13(+6) weeks of gestation, which in our center is performed for the measurement of crown-rump length, nuchal translucency thickness, and fetal heart rate and the examination for major defects. RESULTS: In the 181 fetuses with trisomy 13, there were holoprosencephaly, exomphalos, and/or megacystis in 92 fetuses (50.2%), fetal heart rate above the 95th percentile in 129 fetuses (71.3%), and nuchal translucency above the 95th percentile in 141 fetuses (77.9%). There was no significant association between nuchal translucency and fetal heart rate, and it was estimated that inclusion of fetal heart rate in nuchal translucency screening can improve the detection rate of trisomy 13 by approximately 5%. CONCLUSION: At the 11 to 13(+6)-week scan, the measurement of fetal nuchal translucency and fetal heart rate and fetal examination for holoprosencephaly, exomphalos, and megacystis can identify >90% of fetuses with trisomy 13.

Spatial contouring of risk: a tool for environmental epidemiology.

The possible elevation of disease rates in the proximity of site-specific environmental hazards is much investigated. Single-site studies are subject to problems of reporting bias and statistical power, and multisite studies to heterogeneity of exposure. Both types of studies usually use concentric circular regions centered on a site as a surrogate for defining the exposed and unexposed populations. This approach does not take into account the actual spatial pattern of toxicant dispersion or the spatial pattern associated with the population, and so much useful information is wasted. We report a kernel density technique to map risk contours for disease, which is not influenced by the coordinates of any putative environmental hazard and which could be married to actual spatial exposure patterns.

Centile charts I: new method of assessment for univariate reference intervals.

BACKGROUND: We introduce a new criterion, the percentile inclusion probability, for comparing methods for calculating reference intervals. The criterion is compared with a previously published measure of reliability suggested by Linnet (Linnet K. Clin Chem 1987;33:381-6), the ratio of the width of the confidence interval for the percentile to that of the reference interval. METHODS: Data were simulated from a range of theoretical statistical distributions representing the shapes of data sets encountered in clinical investigations. The two-stage transformation of the data to a gaussian distribution recommended by the IFCC was compared with a nonparametric approach. RESULTS: The percentile inclusion probability criterion identified that the parametric approach is in some cases seriously affected by bias. Using different parametric models, we compared nonparametric and parametric methods for two sets of clinical data and showed that the parametric approach is susceptible to model choice. CONCLUSIONS: Sample sizes significantly greater than those currently recommended are required to establish reference intervals, regardless of whether parametric or nonparametric methods are used. Parametric methods are preferable when the data are truly gaussian, but are only marginally better than nonparametric methods when data transformation is needed to achieve a gaussian shape.

Value of the serum estradiol level for preventing ovarian hyperstimulation syndrome: a retrospective case control study.

OBJECTIVE: To assess the value of different serum E(2) cut-off levels for predicting women at risk for ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective case-control study of a cohort of women undergoing assisted reproduction treatment (ART) over 12 months. SETTING: Tertiary university hospital. PATIENT(S): The study group included women with OHSS who fulfilled the endocrine inclusion criteria (n = 40). The control group was a random sample (n = 40) from the cohort of women undergoing ART. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): To evaluate the sensitivity and specificity of different serum E(2) cut-off levels on day 11 of ovarian stimulation in preventing the establishment of OHSS. RESULT(S): Three hundred ninety-nine cycles (IVF and intracytoplasmic sperm injection) were undertaken between June 2000 and May 2001. The study group (n = 40) was compared with the control group (n = 40) undergoing ART during the same period of time. On day 8 of ovarian stimulation, the mean (SD) E(2) level in the study group was 8,517(5.3) pmol/L (2,320 pg/mL), and in the control group it was 2,540 (2.6) pmol/L (691 pg/mL). On day 11 of stimulation the mean (SD) E(2) level was 15,662 (4.2) pmol/L (4,266 pg/mL) and 5,804 (4.5) pmol/L (1,581 pg/mL), respectively. Twenty-four (60%) women who developed OHSS had E(2)levels >6,000 pmol/L (1,634 pg/mL) on day 8 and above 11,000 pmol/L (2,996 pg/mL) on day 11. Sixteen (40%) had E(2) levels <6,000 pmol/L (1,634 pg/mL) on day 8, but all had levels above 11,000 pmol/l (2,996 pg/mL) on day 11. CONCLUSION(S): A serum E(2) level of 12,315 pmol/L (3,354 pg/mL) on day 11 of ovarian stimulation gives a sensitivity and specificity of 85% for the detection of women at risk for OHSS.

Modeling the hepatitis C virus epidemic in France using the temporal pattern of hepatocellular carcinoma deaths.

Deuffic et al. developed a compartmentalized model that characterized the evolution and spread of the hepatitis C virus (HCV) within France. There were various parameters defining the age- and sex-dependent transition probabilities between chronic hepatitis and cirrhosis in need of determination to completely specify their model. These were estimated by means of a weighted least-squares procedure that was executed numerically. The objective function used was based on the distribution of the age at death from hepatocellular carcinoma (HCC) rather than the temporal pattern of deaths due to HCC from 1979 to 1995. In this report, we investigate the impact of using an objective function based on the temporal pattern of deaths. We show that the dynamics of the epidemic can be quite different, in particular, short-term prediction of HCC deaths by HCV infection and times to death from onset of disease.