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We review the data pertinent to the hypothesis we proposed three decades ago, that all embryos that survive gestation as women with Turner syndrome and have an ostensibly non-mosaic 45,X karyotype, actually are cryptic mosaics for a "rescue line" that includes a viable karyotype. Reanalysis of the prevalence and frequency of 45,X in available data on spontaneous abortuses, and livebirths, confirms prior estimates that 1 % to 1.5 % of all recognizable pregnancies start as an apparent non-mosaic 45,X but about 99 % do not survive gestation. From the rates of 45,X in early embryos, which are notably higher than the inferred rate of gametes hypohaploid for a sex chromosome, as well as the negative maternal age association with 45,X of maternal origin we deduce, in agreement with but on independent grounds from Hall et al. (2006), that a very large proportion of 45,X embryos acquired their 45,X line after fertilization. Results of a search for mosaic cell lines in patients with "Turner syndrome" in several reports indicate that not only does the detection rate of a mosaic line depend upon the number and sensitivity of the markers used, and the number of different tissues examined, but also upon the severity of the phenotype of those cases studied, and the number of cells karyotyped initially. Such factors may explain variation in the extent of detected "cryptic" mosaicism in 45,X individuals (currently at least 50 %). We note a report by Urbach and Benvenitsy (2009) of a gene necessary for placental function, PSF2RA, which lies in the pseudoautosomal-one region of the X and Y chromosomes. Deletion of such a gene could account for the high embryonic lethality in 45,X conceptions, and a rescue line in the placenta could account for embryonic and fetal survival of those cases in which a cryptic mosaic line cannot be found in the usual studies of blood and other tissues from affected individuals. Our primary conclusions are 1) all 45,X individuals with Turner syndrome are cryptic mosaics, 2) absence of the X chromosome in 45,X embryos is caused primarily by mitotic factors, and 3) the placenta is a strong candidate for the location of the rescue line in apparently non-mosaic 45,X individuals.

We have analyzed data on 3,157 cases of Down syndrome (DS) from nine South American countries in consecutive series of hospital live births over a 30-year period, with particular emphasis on possible ethnic or geographic variations in maternal age-adjusted incidence. The data constitute the largest series of DS cases assembled to date from an area lacking advanced health care systems. Absolute incidence rates were estimated from total hospital live births; relative rates were estimated from matched case-control data using conditional logistic regression. Maternal age-adjusted rates were closely similar to those reported elsewhere, and showed little or no dependency on other factors investigated, including paternal age, birth order, ancestral origin, country of birth, maternal educational level, maternal ABO and Rhesus blood groups, interval to and outcome of mother's previous pregnancy, and parental consanguinity. The absence of an effect of high birth order was particularly notable because of the relatively large number of grand multipara resulting from high fertility in this population. The study adds to a body of evidence suggesting that maternal age-adjusted DS rates vary little across human populations, and are therefore unlikely to be greatly influenced by genetic or environmental factors that differ between them. An unusual finding was of a markedly lower sex ratio (98 males per 100 females) than has been reported in other DS samples., (Copyright 2001 Wiley-Liss, Inc.)

The authors used "internal validity analysis" to evaluate the performance of various capture-recapture methods. Data from studies with five overlapping, incomplete lists generated subgroups whose known sizes were compared with estimates derived from various four-source capture-recapture analyses. In 15 data sets unanalyzed previously (five subgroups of each of three new studies), the authors observed a trend toward mean underestimation of the known population size by 16-25%. (Coverage of the 90% confidence intervals associated with the method found to be optimal was acceptable (13/15), despite the downward bias.) The authors conjectured that (with the obvious exception of geographically disparate lists) most data sets used by epidemiologists tend to have a net positive dependence; that is, cases captured by one source are more likely to be captured by some other available source than are cases selected randomly from the population, and this trend results in a bias toward underestimation. Attempts to ensure that the underlying assumptions of the methods are met, such as minimizing (or adjusting adequately) for the possibility of loss due to death or migration, as was undertaken in one exceptional study, appear likely to improve the behavior of these methods.

An exact conditional test for an M-way log-linear interaction in a fully observed 2M contingency table is formulated. From this is derived a procedure for interval estimation of the total count N in a 2M contingency table, one of whose entries is unobserved. This procedure has an immediate application to interval estimation of the size of a closed population from incomplete, overlapping lists of records, as in capture-recapture analysis of epidemiological data. Data on the prevalence of spina bifida in live births in upstate New York in 1969-1974 illustrate this application.

We propose 15 recommendations for approaches to capture-recapture analysis in epidemiology. We apply them to a report of such an analysis of a measles epidemic [McGilchrist et al., J Clinical Epidemiol 1996, 49: 293-296] and to comments thereon by R. C. Cormack [J Clinical Epidemiol 1999; 52: 909-914]. The latter challenged the utility of the data on the measles outbreak for any reliable capture-recapture estimates. We suggest that, adopting the perspective of W. Edwards Deming, one can only make judgments as to the reliability of capture-recapture data, methods, and derived estimates in the light of (i.e., conditional upon) their eventual intended use. Capture-recapture approaches "unreliable" from one perspective may be "reliable," and/or more appropriately, "useful" from another. We consider the utility of ancillary and ad hoc information that may be available or worth seeking to supplement a capture-recapture analysis. We use information within the study of McGilchrist et al. to illustrate how, with such ancillary information, one may overcome the main thrust of the objections of Cormack in situations in which one observes apparently anomalous or hard to understand data structures. Making certain simple assumptions we regard as plausible, we estimate the number of affected in the measles epidemic as between about 700-1300. We derive this from data on 502 cases in a Register, an ad hoc sample of 91 cases in one age group in the general population, and the report of 41 cases in both of these. Our result is only 15-30% the total implied by the estimates McGilchrist et al. derived with more complex methods and many assumptions in addition to our own. We discuss various approaches to evaluating "reliability" of our estimate conditional upon intended uses by policy makers.

Data from the New York State Chromosome Registry on over 10,000 cases of Down syndrome reported from 1977 to 1996 confirm findings in the England and Wales Cytogenetic Register that in mosaic 46/47,+21 cases of Down syndrome the male/female ratio (as inferred from XY and XY karyotypes respectively) is less than 1.0 as opposed to the ratio in nonmosaic 47,+21 cases in which the ratio is close to 1.2, or in the general background population with ratio of about 1.05. These results may reflect in part differential pairing in 47,+21 somatic cells of X and Y chromosomes with a 21 chromosome and/or in in-utero selection.

Reported livebirth prevalence of Down syndrome (DS) may be affected by the maternal age distribution of the population, completeness of ascertainment, accuracy of diagnosis, extent of selective prenatal termination of affected pregnancies, and as yet unidentified genetic and environmental factors. To search for evidence of the latter, we reviewed all published reports in which it was possible to adjust both for effects of maternal age and for selective termination (where relevant). We constructed indices that allowed direct comparisons of prevalence rates after standardising for maternal age. Reference rates were derived from studies previously identified as having near complete ascertainment. An index value significantly different from 1 may result from random fluctuations, as well as from variations in the factors listed above. We found 49 population groups for which an index could be calculated. Methodological descriptions suggested that low values could often be attributed to under-ascertainment. A possible exception concerned African-American groups, though even among these most acceptable studies were compatible with an index value of 1. As we have reported elsewhere, there was also a suggestive increase in rates among US residents of Mexican or Central American origin. Nevertheless, our results suggest that "real" variation between population groups reported to date probably amounts to no more than +/-25%. However, reliable data in many human populations are lacking including, surprisingly, some jurisdictions with relatively advanced health care systems. We suggest that future reports of DS livebirth prevalence should routinely present data that allow calculation of an index standardised for maternal age and adjusted for elective prenatal terminations.

Background: Maternal age-specific rates of Down syndrome livebirths are widely utilized in personal and policy decisions concerning provision of and election of prenatal cytogenetic diagnostic services. The only extensive reference data available are on those of primarily European ancestral origin. In the absence of definitive evidence of any ethnic, racial or environmental influence upon rates (other than those associated with age) these rate schedules have been widely applied to those of all national origins., Methods: Available material age-specific data on livebirths from intensive studies on those of Hispanic (primarily of Mexican and Central American background) and of other origin in populations in the U.S.A. with likely complete ascertainment were analysed. The numbers observed were compared with (i) those predicted from established published rate schedules in those of primarily European origin, and (ii) with the observations on livebirths of non-Hispanic European origin in the same population as the Hispanic live births., Results: In comparisons with the numbers predicted from published rates, observed numbers of case among Hispanic live births were increased by 19 per cent (SE 0.06) in younger mothers, 23 per cent in older mothers (SE 0.07) and 20 per cent (SE 0.04) in those of all ages. Comparisons with observed rates in those of Hispanic origin with those observed in non-Hispanic births in the same time intervals and populations indicated that the excess rates in Hispanics were not attributable to some local factor increasing rates in all ethnic groups at least among those under 35., Conclusions: Data on mothers of Mexican and Central American origin residing in the U.S.A. indicate maternal age-specific rates of Down syndrome in live births about 20 per cent greater than those in published rate schedules on Down syndrome, widely used in decisions concerning election or provison of prenatal diagnostic services. The reason for this difference remains unknown.

Log-linear models for capture-recapture type data are widely used for estimating sizes of populations. Log-linear methods model conditional interactions between the sources. Often, however, the marginal associations are more appropriate and easier for the practitioner to conceptualize. Analyses here of previously published data on cases of spina bifida in upstate New York are used to show how the assumption that sources are conditionally independent can give biased estimates if in fact the sources are marginally independent. A plausible model for the structural sources of interactions between the sources of information about spina bifida cases is developed which implies marginal independence of two of the sources rather than conditional independence. Estimates of the population total based on marginal independence are derived and give larger estimates of the population total than those derived based upon conditional dependence. When investigators can in fact model the likely underlying relationships of the sources in the population, we suggest considering modelling the potential interdependencies of the sources, which we term 'structural source modeling'.

In this paper we present an analysis of nine data sets in which ascertainment and maternal age risk of Down syndrome are estimated jointly using maximum likelihood. We include data on 4825 Down syndrome cases from nine previously published data sets. These include data from studies carried out before the introduction of prenatal screening and from recent studies involving women who had not received prenatal testing. Our results show that, allowing for under-ascertainment, there is a good degree of consistency between the different data sets. We compare the three- and five-parameter constant plus exponential model with a three-parameter logistic model for maternal age-specific risk. We show that the three-parameter logistic model provides a good fit to the data and compare rates from this model with those derived from published studies of uncertain completeness (Cuckle et al., 1987) and those from data sets believed to be complete (Halliday et al., 1995; Hecht and Hook, 1994, 1996). In general, our results agree closely with those of the latter, but achieve greater precision because of the inclusion of additional data. Our derived rates are considerably higher than those of Cuckle et al. (1987), which are embedded in many computer systems for generating risks.

In log-linear capture-recapture approaches to population size, the method of model selection may have a major effect upon the estimate. In addition, the estimate may also be very sensitive if certain cells are null or very sparse, even with the use of multiple sources. The authors evaluated 1) various approaches to the issue of model uncertainty and 2) a small sample correction for three or more sources recently proposed by Hook and Regal. The authors compared the estimates derived using 1) three different information criteria that included Akaike's Information Criterion (AIC) and two alternative formulations of the Bayesian Information Criterion (BIC), one proposed by Draper ("two pi") and one by Schwarz ("not two pi"); 2) two related methods of weighting estimates associated with models; 3) the independent model; and 4) the saturated model, with the known totals in 20 different populations studied by five separate groups of investigators. For each method, we also compared the estimate derived with or without the proposed small sample correction. At least in these data sets, the use of AIC appeared on balance to be preferable. The BIC formulation suggested by Draper appeared slightly preferable to that suggested by Schwarz. Adjustment for model uncertainty appears to improve results slightly. The proposed small sample correction appeared to diminish relative log bias but only when sparse cells were present. Otherwise, its use tended to increase relative log bias. Use of the saturated model (with or without the small sample correction) appears to be optimal if the associated interval is not uselessly large, and if one can plausibly exclude an all-source interaction. All other approaches led to an estimate that was too low by about one standard deviation.

The identification of an apparent excess of a genetic outcome in a particular area and/or a particular time often provokes considerable public alarm about the presence of an environmental mutagen. It is often difficult to determine in any particular case whether the observation, whatever its nominal statistical significance, is due to chance concatenation of events or to an environmental factor. Statistical evaluation is made more difficult by the profuse number of possible hypotheses that could have triggered concern about an excess. This renders it difficult to calculate the actual probability of the observation (or one more extreme). By attempting to identify similar types of outcomes that could have provoked an apparent excess and then undertaking computer simulations assuming random deviations from a constant rate, one may attempt to adjust for the problem of multiple hypotheses. We apply this approach to a reported excess of Down's syndrome in Norway in 1985-1986 in younger mothers, and conclude that there is a high probability that it arose by chance.

Objective: To determine whether high levels of serum alpha-fetoprotein (AFP) predict increased risk of adverse pregnancy outcomes, including preterm birth (before 37 weeks), preterm birth occurring at or before 28 weeks, small for gestational age (SGA) infant, preeclampsia, and placental abnormalities, and to determine whether low levels of serum AFP predict increased or decreased risk of these outcomes., Methods: Using the mother's first name, last name, and zip code, we linked the records of 51,008 women who participated in the California Alpha-Fetoprotein Screening Program between June 15, 1986, and October 31, 1987, with California birth certificates for singleton infants born in 1987. The accuracy of the data linkage was confirmed by manually examining complete names, mother's ethnicity, and mother's age for a sample of 500 of the mother-infant linkages. Blood samples were obtained at 15-19 weeks., Results: A strong gradient of increasing risk of preterm birth with increasing levels of serum AFP was observed (test for trend, P < .01). Among women with high levels of serum AFP (at least 2.5 multiples of the median [MoM]), 24.3% had preterm births, compared with 3.8% of women with low levels of serum AFP (0.81 MoM or less), odds ratio 8.7, 95% confidence interval 7.1-10.7). This gradient persisted when preterm infants of 28 weeks or less were examined separately. Similar gradients were observed for the risk of preeclampsia and placental abnormalities. There was a weaker U-shaped relation between serum AFP level and the risk of an SGA infant., Conclusion: Low levels of second-trimester maternal serum AFP are associated with a very low risk of preterm birth, preeclampsia, and placental complications. High levels of serum AFP are strongly associated with preterm birth, preeclampsia, and placental abnormalities. There is a modest association between AFP levels (both low and high) and SGA birth.

Data from the National Down Syndrome Cytogenetic Register is used to describe the cytogenetics and epidemiology of registered cases. The register comprises notifications from cytogenetics laboratories in England and Wales. This report is of 5737 cases registered between 1989 and 1993: 2169 prenatal and 3436 postnatal diagnoses, and 132 spontaneous abortions. Eighty eight registrations were from multiple pregnancies. Ninety five percent had regular trisomy 21. In 4% there was a translocation, mostly Robertsonian t(14;21) or t(21;21). One percent were mosaics with one normal cell line. Mean maternal age was raised in free trisomy 21, but not in translocations. Where families had been investigated, about a third of translocations were inherited, six to seven times more often from the mother than the father. Associations between free trisomy 21 and structural chromosomal defects in the births were no more common than expected from newborn series. The overall sex ratio was raised (male to female: 1.23 to 1), and there was an excess of associated male sex chromosomal aneuploidy. However, in mosaics with one normal cell line the male to female ratio was 0.8 to 1, and in twins discordant for trisomy 21 there was also a female excess.

Precision and accuracy in determining rates of Down syndrome at livebirth are indispensible to algorithms which determine eligibility for prenatal cytogenetic diagnostic services. We derived Down syndrome rates by single year of maternal age which we propose as a revised rate schedule for background risk. Data on European-origin populations were obtained from 5 sources judged most likely to have complete ascertainment of cases. A "constant plus exponent" regression model and variants extending the analysis to higher powers of maternal age were applied to several ranges of maternal age. Confidence intervals about the rates were calculated. This analysis results in rates significantly higher than those in widespread use though the confidence intervals show a need for caution in assuming precision. Sources of variation in rates are also considered.

The authors propose a method for adjusting results of log-linear multi-source capture-recapture estimates of total population. The method compares the totals in some subpopulations of known size with estimates derived from various capture-recapture approaches to these subpopulations. The authors term such an approach an "internal validity analysis". Trends in the ratios of the estimates to the known true values of these subpopulations provide a plausible indicator of the bias of some types of estimates of the total population especially when underlying assumptions of the methods used have not been met in analysis of the total population. The authors apply this method to published data on an open population of injection drug users that had been previously analyzed with a standard capture-recapture analysis as if it were a closed population. Internal validity analysis suggests that the size of this population is about 15% greater than that previously estimated.

The pregnancy outcomes on cases of Down syndrome diagnosed prenatally in which the mother did not elect termination were evaluated in data reported to a comprehensive Register of Down syndrome for England and Wales for 1989-94. In the 168 cases in which placental biopsy was not used, the overall rate of spontaneous loss was 35%, but this figure masks considerable heterogeneity by gestational stage at ascertainment. Data on ages at diagnostic procedure and on pregnancy termination enabled a more precise survival analysis. The loss rates were approximately 50% for those fetuses ascertained at 15-17 completed wk, 43% at 18 wk, 31% at 19 wk, 25% at 20 wk, and then a leveling off at approximately 20%-25% for fetuses ascertained at 21-28 completed wk. For fetuses ascertained prior to 18 wk, there was no evidence that maternal age was associated with fetal loss, consistent with earlier reports. At 18 wk and after, however, maternal age was on the average approximately 3 years greater in fetuses that were lost. Comparison of successive gestational birth cohorts provided no evidence in these 168 cases that the diagnostic procedure itself had any effect on loss or that selective ascertainment of mothers in risk of loss had any effect on the results. In contrast, in the 21 cases in which placental biopsy had been undertaken, the overall loss rates were not only higher when appropriate comparisons could be made, but there was some evidence for selective ascertainment and/or procedure-associated losses.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To study the chromosome abnormality rate among women with elevated levels of maternal serum alpha-fetoprotein (MSAFP) and the types of chromosome abnormalities in this population, and to compare this rate with reports in the literature and the rate observed in the general population., Methods: We studied 8097 women who chose to undergo amniocentesis and fetal karyotyping after having an elevated MSAFP test of 2.5 multiples of the median (MOM) or higher. All abnormal karyotypes were reviewed and grouped according to whether the elevated MSAFP value could be explained by a ventral wall or neural tube defect., Results: The overall chromosome abnormality rate was 13.83 per 1000 amniocenteses. The rate in the "unexplained" group was 10.92 per 1000 amniocenteses. Just over half (53%) of the abnormal karyotypes were autosomal anomalies, and 47% were sex chromosome abnormalities. The autosomal aneuploidies observed most frequently were triploidy and trisomy 13. The sex chromosome abnormalities observed most frequently were the XXY and XYY karyotypes., Conclusion: Women who have unexplained elevated MSAFP values of 2.5 MOM or greater have a twofold increase in the rate of chromosome abnormalities in their fetuses compared with the general population (P < or = .001). This rate is consistent with other studies that used a 2.5 MOM cutoff. Studies that used a 2.0 MOM cutoff have reported chromosome abnormality rates that do not vary from general population estimates.

Capture-recapture methods were used to estimate the prevalence of fetal alcohol syndrome among Alaska Natives born during the period 1982-1989. Potential cases were identified through an Indian Health Service (IHS) patient case file, a pediatric practice case file, and Medicaid claims from private physicians. A total of 74 Alaska Native children aged 3-10 years were identified with a notation of fetal alcohol syndrome by a physician in a medical record. Because not all of these cases had supporting documentation regarding the syndrome, they were classified as possible cases. Of these possible cases, 50 met all five criteria for chart verification of the syndrome: physician notation of fetal alcohol syndrome, growth deficiency, facial features of the syndrome, central nervous system impairment, and a maternal history of alcohol abuse. These data provided observed prevalence rates of chart-verified fetal alcohol syndrome of 3.1 per 1,000 live births for children born 1982-1985 (age 7-10 years), and 2.0 per 1,000 live births for children born 1986-1989 (age 3-6 years). Capture-recapture analyses were conducted using cases identified by IHS and private physicians. These analyses estimated a prevalence of the syndrome of 3.8 per 1,000 live births for children born 1982-1985, and 3.1 per 1,000 live births for children born 1986-1989. Based on the capture-recapture predicted number of cases, the IHS case file ascertained a greater percentage of cases among the older cohort (75%) than among the younger cohort (56%). These data illustrate the use of capture-recapture analyses in identifying the extent to which observed trends in rates may reflect differences in cases ascertainment over time (or by birth cohort). The application of capture-recapture in fetal alcohol syndrome surveillance, however, requires careful attention to the underlying assumptions of capture-recapture methods.

Current algorithms to determine eligibility for prenatal cytogenetic diagnostic services depend critically on the accuracy and precision of the underlying rates of cytogenetic abnormality used in the calculations. We examine the maternal age-specific rates of Down syndrome livebirths in eight studies of European-origin populations, pooled rates from which are widely used for baseline calculations in biochemical screening. These studies vary significantly in such factors as methods of ascertainment of cases, likelihood of complete ascertainment, and methods of correction, if any, for underascertainment. Restriction of analysis to those two studies among the eight whose methods suggest the greatest likelihood of complete ascertainment for Down syndrome generates rates significantly higher than those in widespread use. Confidence intervals about previously reported and currently derived rates indicate that even with large-scale data, there is considerable residual uncertainty in derived rates.

In data of the U.S. Collaborative Perinatal Study (CPS), the Drug Epidemiology Unit (DEU) reported a relative risk of about 2.3 between maternal female sex hormone exposure during months 1 to 4 of pregnancy and cardiovascular malformation in infants (Heinonen et al., '77a N. Engl. J. Med., 296:67-70). Wiseman and Dodds-Smith ('84, Teratology, 30:359-370) reexamined the original CPS data and found the DEU had made some errors in classification of exposure and disease. Also they challenged the classification of cases as "exposed" in those born to mothers who received the compounds outside the day 19 to 50 window of cardiovascular embryogenesis. Wiseman and Dodds-Smith stated that their reanalysis "clearly showed that there was [in the data used by the DEU] no statistically significant association between exposure in the critical organogenic period of pregnancy and cardiac malformation in offspring." They did not undertake any statistical analysis, but their reanalysis resulted in a wide-spread nonacceptance of the association reported by the DEU. The study reported here reclassified the cases of the original DEU study in accord with the implications of the Wiseman and Dodds-Smith reanalysis of exposure and disease. After this reclassification, an effect magnitude measure of association, the relative risk rose from 2.33 to 2.48 and remained nominally significant statistically at the .05 level. Thus, if anything, the quantitative consequences of the Wiseman and Dodds-Smith review of the data, when applied in an unbiased manner, result in an increase in the measure of effect.(ABSTRACT TRUNCATED AT 250 WORDS)