National Down Syndrome Cytogenetic Register Research Articles

Prevalence of Down's Syndrome in England, 1998-2013: Comparison of linked surveillance data and electronic health records.

IntroductionDisease registers and electronic health records are valuable resources for disease surveillance and research but can be limited by variation in data quality over time. Quality may be limited in terms of the accuracy of clinical information, of the internal linkage that supports person-based analysis of most administrative datasets, or by errors in linkage between multiple datasets.ObjectivesBy linking the National Down Syndrome Cytogenetic Register (NDSCR) to Hospital Episode Statistics for England (HES), we aimed to assess the quality of each and establish a consistent approach for analysis of trends in prevalence of Down’s syndrome among live births in England.MethodsProbabilistic record linkage of NDSCR to HES for the period 1998–2013 was supported by linkage of babies to mothers within HES. Comparison of prevalence estimates in England were made using NDSCR only, HES data only, and linked data. Capture-recapture analysis and quantitative bias analysis were used to account for potential errors, including false positive diagnostic codes, unrecorded diagnoses, and linkage error.ResultsAnalyses of single-source data indicated increasing live birth prevalence of Down’s Syndrome, particularly in the analysis of HES. Linked data indicated a contrastingly stable prevalence of 12.3 (plausible range: 11.6–12.7) cases per 10 000 live births.ConclusionCase ascertainment in NDSCR improved slightly over time, creating a picture of slowly increasing prevalence. The emerging epidemic suggested by HES primarily reflects improving linkage within HES (assignment of unique patient identifiers to hospital episodes). Administrative data are valuable but trends should be interpreted with caution, and with assessment of data quality over time. Data linkage with quantitative bias analysis can provide more robust estimation and, in this case, stronger evidence that prevalence is not increasing. Routine linkage of administrative and register data can enhance the value of each.KeywordsDown’s syndrome; data linkage; disease surveillance; linkage error; electronic health records; prevalence

Prevalence three ways: Comparison of linked data from a patient register and electronic health records with allowance for linkage error

Background with rationalePatient registers and electronic health records are both valuable resources for disease surveillance but can be limited by variation in data quality over time. Variation may stem from changes in data collection methods, in the accuracy or completeness of clinical information, or in the quality of patient identifiers and the linkage that relies on these.
 Main AimBy linking the National Down Syndrome Cytogenetic Register (NDSCR) to Hospital Episode Statistics for England (HES), we aimed to assess the quality of each and establish a consistent approach for analysis of trends in prevalence of Down’s syndrome among live births in England.
 Methods/ApproachProbabilistic record linkage of NDSCR to HES for the period 1998–2013, supported by linkage of babies to mothers within HES. Comparison of prevalence estimates in England using NDSCR only, HES data only, and linked data. Capture-recapture analysis and quantitative bias analysis were used to account for potential errors, including false positive diagnostic codes, unrecorded diagnoses, and linkage error.
 ResultsAnalyses of single-source data indicated increasing live birth prevalence of Down’s syndrome, particularly steep in analysis of HES. Linked data indicated a contrastingly stable prevalence of 12.3 cases per 10,000 live births, with a plausible range of 11.6–12.7 cases per 10,000 live births allowing for potential errors.
 Conclusion Case ascertainment in NDSCR improved slightly over time, creating a picture of slowly increasing prevalence. The emerging epidemic suggested by HES primarily reflects improving linkage within HES (assignment of unique patient identifiers to hospital episodes). Administrative data are valuable but trends should be interpreted with caution, and with assessment of data quality over time. Linked data with quantitative bias analysis can provide more robust estimation and, in this case, reassurance that prevalence of Down’s syndrome is not increasing. Routine linkage of administrative and register data can enhance the value of each.

Accuracy of reporting abortions with Down syndrome in England and Wales: a data linkage study

The number of abortions of fetuses with Down syndrome in England and Wales reported by the Department of Health (DH) differs from that reported by the National Down Syndrome Cytogenetic Register (NDSCR). The aim of this study was to investigate the reasons for this. Abortions in 2011 and 2012 from DH were matched to those from NDSCR. The number of cases not reported to either source was estimated. An estimated 2240 abortions of fetuses with Down syndrome occurred in 2011/12; NDSCR estimated 2208 and DH 1100. One thousand and six abortions were identified in both data sets, including 145 (14%) which were not recorded by DH as having Down syndrome. Abortions in NDSCR that were not matched in DH occurred throughout England and Wales and at all gestational ages. An estimated 61 abortions of fetuses with Down syndrome were not reported to DH or NDSCR. The number of abortions of fetuses with Down syndrome reported by the NDSCR is more complete than that reported by the DH. DH data for abortions with other congenital anomalies are also likely to be underestimates, and more accurate estimates are available from BINOCAR regional congenital anomaly registers.

Survival of trisomy 18 (Edwards syndrome) and trisomy 13 (Patau Syndrome) in England and Wales: 2004–2011

The aim of this study is to determine the survival of live births with trisomy 18 and trisomy 13 and their variants. Information on live births with trisomy 18 or trisomy 13 recorded in the National Down Syndrome Cytogenetic Register (NDSCR) was linked by the NHS Information Centre to obtain information about survival. Survival was known for 326 (88%) of live births with trisomy 18 and 142 (82%) of live births with trisomy 13 born in England and Wales between 2004 and 2011. The median survival time for live births with full trisomy 18 was 14 days and with full trisomy 13 was 10 days, the 3-month survival was 20% and 18%, respectively, and the 1-year survival for both syndromes was 8%. The 1-year survival for live births with trisomy 18 mosaicism (n = 17) was 70%, for those with trisomy 13 mosaicism (n = 5) was 80% and for those with partial trisomy 13 (Robertsonian translocations) (n = 17) was 29%. This study is based on the largest data set on survival for live births with trisomy 18 and trisomy 13. Although median survival for these children is 2 weeks or less, about one in five survive for 3 months or more and about 1 in 12 survive for 1 year or more. We suggest that these survival rates are used in counselling as well as the median survival time.

Cytogenetic and epidemiological findings in Down syndrome: England and Wales 1989–2009

This study describes the characteristics of karyotypes leading to phenotypic Down syndrome (trisomy 21) in 29,256 cases diagnosed between 1989 and 2009 in England and Wales included in the National Down Syndrome Cytogenetic Register (NDSCR). The frequency of occurrence of the different karyotypes, proportions diagnosed prenatally, sex ratios, mean maternal age, and proportions of mothers with recurrences were analyzed. Nearly 97% of all cases were free trisomy 21; 2.9% contributory trisomy 21, 0.3% double or triple aneuploidies; 1% of all were mosaics. Mean maternal age of free trisomy 21 cases was 35 years, 54% were male, and 1% of mothers had recurrences. Free trisomy 21 mosaics had a lower mean maternal age (33 years), a lower proportion of males (39.5%), and 2.5% of mothers had recurrences. The majority of contributory translocations were Robertsonian or rea (21;21). Their mothers were younger, particularly those of Robertsonian translocations (28 years). Of the Robertsonian der (14;21) translocations of known parental origin, 54% were de novo, 41% maternal and 5% paternal and 15.8% of mothers of those of maternal origin had recurrences. Multiple aneuploidies have the highest proportion of males (67%), highest proportion of mosaics (40%), a mean maternal age of 37 years, and no mothers had a recurrence. The size of this national register allowed the frequency of occurrence of the rarer karyotypes of Down syndrome to be estimated and their epidemiology described.

Stability of U.K. Down Syndrome Birth Rate: Age-Related Risks Offset by Antenatal Screening

The U.K.'s National Down Syndrome Cytogenetic Register has received data on all ante- or postnatal diagnoses of Down syndrome in England and Wales since 1989. During that time, incidence of antenatally diagnosed Down syndrome rose by 71%. The largest increase occurred after 2001, when the U.K. National Screening Committee …

Ascertainment and accuracy of Down syndrome cases reported in congenital anomaly registers in England and Wales

Objective:Congenital anomaly registers allow the rates of anomalies to be monitored and are essential for understanding their epidemiology. We estimate the ascertainment and accuracy of records of Down syndrome (DS)...

The proportions of Down's syndrome pregnancies detected prenatally in England and Wales from 1989 to 2004

The proportion of Down's syndrome pregnancies detected prenatally in England and Wales is lower in younger mothers than in older mothers. This paper examines the reasons for this apparent age inequality. We used data from the National Down Syndrome Cytogenetic Register (NDSCR) to examine the time trend of the proportion of Down's syndrome pregnancies diagnosed prenatally according to maternal age over the years 1989-2004 in England and Wales. A lower proportion of younger mothers had their Down's syndrome pregnancy detected prenatally than older mothers; however, this gap has been closing over time. For example, for mothers under 25 years of age only 13% of Down's syndrome pregnancies were detected prenatally from 1989 to 1992, with this figure rising to 34% in 2001-2004, compared with proportions of 74% in both periods for mothers over 44 years of age. A lower uptake of screening among younger women could not explain these differences. The differences in detection rates of the screening methods according to maternal age, particularly of the older screening tests, could account for these differences. The closing gap between the proportions of younger and older women having their affected pregnancy prenatally diagnosed is a confirmation of the improvement of screening methods over time.

Downʼs Syndrome in Births Near Landfill Sites

P-286 Introduction: Excess risk of non-chromosomal congenital anomalies near landfill sites in Great Britain has previously been reported. Some studies on chromosomal congenital anomalies in relation to waste handling processes have indicated small excess risks of Down's syndrome. The aim of the present study was to investigate the risk of giving birth to a baby with Down's syndrome in populations living near landfill sites. Methods: We used the National Down Syndrome Cytogenetic Register (NDSCR) which includes data on Down's syndrome cases in England and Wales. We used national postcoded birth data and NDSCR registrations for the years 1989–1998 complemented by Terminations data (1992–1998) due to Grounds E (risk of foetal handicap). We used distance from postcode of residence to landfill sites to assess potential exposure. Data provided by the national regulatory agencies were merged in a geographical information system to give a database containing 17 752 sites. We constructed a 2 km zone around each site, giving a resolution similar to or higher than that of previous studies, and at the likely limit of dispersion for landfill emissions. People living more than two km from all known landfill sites during the study period comprised the reference population. A ‘near vs. reference’ analysis was implemented within a Bayesian model, calculating expected numbers in the near area based on covariate-adjusted rates estimated from the reference data using a generalised linear model. Results: We found no excess risks of Down's syndrome related to landfill sites (RR= 1.009 (95% confidence interval 0.903–1.116). There were no differences in risk between sites licensed to carry special (= hazardous) waste and other sites. Discussion and Conclusions: Chromosomal congenital anomalies may result from long-term exposure to potential hazards in contrast to non-chromosomal anomalies, which would only be affected by exposures during pregnancy. Assuming a long latency and migration over a long period of time, this would most likely result in substantial exposure misclassification; hence results in our study (and others) may be biased towards the null. Some reports have indicated that low socio-economic status increases the risk of giving birth to a baby with Down syndrome. However, the small changes in risk after adjustment for deprivation in our study supports the concept that factors associated with deprivation, such as smoking, do not strongly influence risk of Down's syndrome. In conclusion, we found no evidence that living near a landfill increases the risk of having a baby with Down syndrome.

Recurrences of free trisomy 21: analysis of data from the National Down Syndrome Cytogenetic Register

To determine the recurrence risk of a free trisomy 21 pregnancy. Data from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all cases of Down syndrome between 1989 and 2001 in England and Wales were used. Among 11 281 women with a Down syndrome pregnancy who had had at least one previous pregnancy there were 95 women who had had a previous Down syndrome pregnancy. Women who have had a previous Down syndrome pregnancy have a constant absolute excess risk above their maternal age-related risk of having a subsequent affected pregnancy. This absolute excess risk is determined by the age at which the affected pregnancy occurred and is higher for younger than for older women. For example, after a Down syndrome pregnancy at age 20, this excess is 0.62% (95% CI: 0.24 to 1.15%) at early second trimester, and, after one at age 40, it is 0.04% (95% CI: 0.01 to 0.07%). More precise risk estimates by single year of maternal age for use in genetic counselling are provided, but they need validation from other studies before they are incorporated in the risk estimation routines used in Down syndrome screening programmes.

Epidemiology of double aneuploidies involving chromosome 21 and the sex chromosomes

The chance of two chromosome abnormalities occurring in one conceptus is very small. However, some authors have suggested that double aneuplodies (DAs) might be more common than the product of their individual frequencies. The nonrandomness of such DA events was considered to be evidence that nondisjunction (NDJ) may be genetically determined. Data collected from the National Down syndrome Cytogenetic Register (NDSCR) in England and Wales and from the literature indicate that the frequencies of all nonmosaic DAs, except for 48,XXY,+21, are lower than expected, probably because of strong intrauterine selection against such pregnancies. Collectively, we identified 52 cases of nonmosaic 48,XXY,+21; 28 cases of 48,XYY,+21; and 14 cases of 48,XXX,+21 in liveborns and 13 cases of 48,XXY,+21; four cases of 48,XYY,+21; and two cases of 48,XXX,+21 after prenatal diagnoses. Among these cases, analysis of the published unbiased cytogenetic surveys of liveborn DS revealed 24 cases of 48,XXY,+21; nine cases of 48,XYY,+21; and seven cases of 48,XXX,+21. These figures are different from the expected proportion of 1:1:1 (P < 0.001), with carriers of XXY overrepresented in the group of carriers of DA. Mechanisms put forth to account for the higher occurrence of 48,XXY,+21 may include greater accessibility of disomic ovum to Y-carrying sperm, and promotion of NDJ in ovum by Y-bearing sperm. 48,XXY,+21 DA was found to be age-dependent, as the proportion of mothers over age 35 (x = 33.0) was increased over the general population. This is in contrast to the apparently age-independent 48,XYY,+21 DA, with a mean maternal age of 24.7 (P < 0.001). Paternal ages were also remarkably different between the groups, with a mean age of 37.9 in 48,XXY,+21 cases and a mean age of 27.9 in 48,XYY,+21 cases (P < 0.01). Maternal age-related factors, rather than genetic predisposition, may play a more important role in the etiology of the most common DA, 48,XXY,+21.

Revised estimates of the maternal age specific live birth prevalence of Down's syndrome.

To revise the estimates of maternal age specific live birth prevalence of Down's syndrome in the absence of antenatal screening and selective termination using newly available data. Data were used from the National Down Syndrome Cytogenetic Register (NDSCR), which contains information on nearly all antenatally or postnatally diagnosed cases of Down's syndrome in which a karyotype was confirmed between 1989 and 1998 in England and Wales. It is the largest single series of data on the prevalence of Down's syndrome. The prevalence does not continue increasing at an increasing rate with age above age 45 as has been previously assumed. Above this age the rate of increase declines with increasing age. The overall age pattern is sigmoidal. A new logit logistic model is proposed which fits the data well. The risk of a Down's syndrome live birth is given by: risk=1/(1+exp(7.330-4.211/(1+exp(-0.282x(age-37.23))))).