Richard J. Silverwood

Statistical methods for constructing gestational age-related reference intervals and centile charts for fetal size.

Many fetal size variables, for example head measurements, abdominal measurements and femur length, increase over the course of gestation. Reference intervals (RIs) and centile charts provide a means of assessing these measurements, at a given gestational age (GA) or across a range of GAs, respectively, and are tools of great importance in clinical medicine. RIs (sometimes, misleadingly, called ‘normal ranges’) represent the interval between a pair of symmetrically placed extreme centiles (such as the 5th and 95th for a 90% interval) of a size variable, denoted y, at a given GA. Centile charts plot the values of y corresponding to one or more RIs against the relevant GA over a range of GAs. In the field of fetal size, values which lie outside the RI are regarded as extreme and may indicate the presence of a disorder such as intrauterine growth restriction1 or macrosomia2. More informative, however, than this forced dichotomy is the calculation of a value’s centile position, or Z-score, relative to the reference population, estimated from knowledge of the distribution of y at a given GA. For a given observation, the proximity of the centile position to 0% or 100% (alternatively the magnitude and sign of the Z-score) is then a measure of how extreme the observation is compared to the reference data at that GA. A centile position above 50% (equivalently a positive Z-score) signifies a measurement greater than average for that GA, and a centile position below 50% (or a negative Z-score) one less than average. While recent years have seen the publication of a variety of strategies for the construction of RIs, incorrect methods have still been used for fetal measurements of all kinds1. The choice of suitable methodology in this field is especially crucial as inaccurate centiles may lead to false conclusions regarding the development of the fetus, resulting in suboptimal clinical care. In an article in this issue of the Journal, Sherer et al.3 construct centile charts of the axial cerebellar hemisphere circumference (CHC) and area (CHA) through gestation using one such method, based upon regression modelling of both the mean and the standard deviation (SD) across GA, as detailed by Altman and Chitty4 and Royston and Wright1. It is the aim of the present article to further examine the statistical approach used by Sherer et al.3, while taking a more general look at the problem of constructing GArelated RIs and considering alternative approaches to this problem. Techniques for longitudinal data, where each subject contributes repeated observations, as opposed to cross-sectional data, where they contribute only one, require a different approach and are not considered here. Further information on this area can be found in, for example, Royston and Altman5 and Royston6. While many of the techniques explored here could be, and indeed have been, used in the context of anthropometric measurements, the focus here is on applications in the field of fetal size.

BMI peak in infancy as a predictor for later BMI in the Uppsala Family Study

Background:The development of obesity through childhood, often characterized by using body mass index (BMI), has received much recent interest because of the rapidly increasing levels of obesity worldwide. However, the extent to which the BMI trajectory in the first year of life (the BMI ‘peak’ in particular) is associated with BMI in later childhood has received little attention.Subjects:The Uppsala Family Study includes 602 families, comprising mother, father and two consecutive singleton offspring, both of whom were delivered at the Uppsala Academic Hospital, Sweden, between 1987 and 1995. The childrens postnatal growth data, including serial measurements of height and weight (from which BMI was calculated), were obtained from health records. All children had a physical examination when they were aged between 5 and 13 years, at which height and weight were again recorded and used to calculate age- and sex-adjusted BMI z-scores.Methods:Subject-specific growth curves were fitted to the infant BMI data using penalized splines with random coefficients, and from these the location of the BMI peak for each participant was estimated. A multilevel modelling approach was used to assess the relationships between the BMI peak and BMI z-score in later childhood.Results:The BMI peak occurred, on average, slightly later in female children, with a higher BMI peak in male children. Considered separately, both age and BMI at BMI peak were positively associated with later BMI z-score. Considered jointly, both dimensions of BMI peak retained their positive associations.Conclusions:The growth trajectory associated with higher childhood BMI appears to include a later and/or higher BMI peak in infancy.

Association between Younger Age When First Overweight and Increased Risk for CKD

There is little information on how the duration of overweight or obesity during life affects the risk for CKD. To investigate whether prolonged exposure to overweight during adult life increases the risk of later CKD in a cumulative manner, we analyzed data from the Medical Research Council National Survey of Health and Development, a socially stratified sample of 5362 singleton children born in 1 week in March 1946 in England, Scotland, and Wales. Multiple imputation expanded the analysis sample from the initial 1794 participants with complete data to 4584. This study collected self-reported body mass index (BMI) at ages 20 and 26 years and measured BMI at ages 36, 43, 53, and 60-64 years. The outcome of interest was CKD at age 60-64 years, suggested by estimated GFR (eGFR) <60 ml/min per 1.73 m(2) and/or urine albumin-to-creatinine ratio (UACR) ≥ 3.5 mg/mmol. In analyses adjusted for childhood and adulthood social class, first becoming overweight at younger ages was associated with higher odds of developing CKD by age 60-64 years. Compared with those who first became overweight at age 60-64 years or never became overweight, those first overweight at age 26 or 36 years had approximately double the odds of developing CKD. The strength of this association decreased with increasing age when first overweight (P for trend <0.001). These associations were consistent for creatinine-based eGFR, cystatin C-based eGFR, and UACR. Taken together, these results suggest that preventing overweight in early adulthood may have a considerable effect on the prevalence of CKD in the population.

Low birth weight, later renal function, and the roles of adulthood blood pressure, diabetes, and obesity in a British birth cohort

Low birth weight has been shown to be associated with later renal function, but it is unclear to what extent this is explained by other established kidney disease risk factors. Here we investigate the roles of diabetes, hypertension, and obesity using data from the Medical Research Council National Survey of Health and Development, a socially stratified sample of 5362 children born in March 1946 in England, Scotland, and Wales, and followed since. The birth weight of 2192 study members with complete data was related to three markers of renal function at age 60–64 (estimated glomerular filtration rate (eGFR) calculated using cystatin C (eGFRcys), eGFR calculated using creatinine and cystatin C (eGFRcr-cys), and the urine albumin–creatinine ratio) using linear regression. Each 1 kg lower birth weight was associated with a 2.25 ml/min per 1.73 m2 (95% confidence interval 0.80–3.71) lower eGFRcys and a 2.13 ml/min per 1.73 m2 (0.69–3.58) lower eGFRcr-cys. There was no evidence of an association with urine albumin–creatinine ratio. These associations with eGFR were not confounded by socioeconomic position and were not explained by diabetes or hypertension, but there was some evidence that they were stronger in study members who were overweight in adulthood. Thus, our findings highlight the role of lower birth weight in renal disease and suggest that in those born with lower birth weight particular emphasis should be placed on avoiding becoming overweight.

Association of Higher Parental and Grandparental Education and Higher School Grades With Risk of Hospitalization for Eating Disorders in Females The Uppsala Birth Cohort Multigenerational Study

Eating disorders are a leading cause of disease burden among young women. This study investigated associations of social characteristics of parents and grandparents, sibling position, and school performance with incidence of eating disorders. The authors studied Swedish females born in 1952-1989 (n = 13,376), third-generation descendants of a cohort born in Uppsala in 1915-1929. Data on grandparental and parental social characteristics, sibling position, school grades, hospitalizations, emigrations, and deaths were obtained by register linkages. Associations with incidence of hospitalization for eating disorders were studied with multivariable Cox regression, adjusted for age and study period. Overall incidence of hospitalization for eating disorders was 32.0/100,000 person-years. Women with more highly educated parents and maternal grandparents were at higher risk (hazard ratio for maternal grandmother with higher education relative to elementary education = 6.5, 95% confidence interval: 2.2, 19.3, adjusted for parental education). Independent of family social characteristics, women with the highest school grades had a higher risk of eating disorders (hazard ratio = 7.7, 95% confidence interval: 2.5, 24.1 for high compared with low grades in Swedish, adjusted for parental education). Thus, higher parental and grandparental education and higher school grades may increase risk of hospitalization for eating disorders in female offspring, possibly because of high internal and external demands.

Testing for non-linear causal effects using a binary genotype in a Mendelian randomization study: application to alcohol and cardiovascular traits

Background: Mendelian randomization studies have so far restricted attention to linear associations relating the genetic instrument to the exposure, and the exposure to the outcome. In some cases, however, observational data suggest a non-linear association between exposure and outcome. For example, alcohol consumption is consistently reported as having a U-shaped association with cardiovascular events. In principle, Mendelian randomization could address concerns that the apparent protective effect of light-to-moderate drinking might reflect ‘sick-quitters’ and confounding. Methods: The Alcohol-ADH1B Consortium was established to study the causal effects of alcohol consumption on cardiovascular events and biomarkers, using the single nucleotide polymorphism rs1229984 in ADH1B as a genetic instrument. To assess non-linear causal effects in this study, we propose a novel method based on estimating local average treatment effects for discrete levels of the exposure range, then testing for a linear trend in those effects. Our method requires an assumption that the instrument has the same effect on exposure in all individuals. We conduct simulations examining the robustness of the method to violations of this assumption, and apply the method to the Alcohol-ADH1B Consortium data. Results: Our method gave a conservative test for non-linearity under realistic violations of the key assumption. We found evidence for a non-linear causal effect of alcohol intake on several cardiovascular traits. Conclusions: We believe our method is useful for inferring departure from linearity when only a binary instrument is available. We estimated non-linear causal effects of alcohol intake which could not have been estimated through standard instrumental variable approaches.

Characterizing Longitudinal Patterns of Physical Activity in Mid-Adulthood Using Latent Class Analysis: Results From a Prospective Cohort Study

The authors aimed to describe how longitudinal patterns of physical activity during mid-adulthood (ages 31–53 years) can be characterized using latent class analysis in a population-based birth cohort study, the Medical Research Council’s 1946 National Survey of Health and Development. Three different types of physical activity—walking, cycling, and leisure-time physical activity—were analyzed separately using self-reported data collected from questionnaires between 1977 and 1999; 3,847 study members were included in the analysis for one or more types of activity. Patterns of activity differed by sex, so stratified analyses were conducted. Two walking latent classes were identified representing low (52.8% of males in the cohort, 33.5% of females) and high (47.2%, 66.5%) levels of activity. Similar low (91.4%, 82.1%) and high (8.6%, 17.9%) classes were found for cycling, while 3 classes were identified for leisure-time physical activity: “low activity” (46.2%, 48.2%), “sports and leisure activity” (31.0%, 35.3%), and “gardening and do-it-yourself activities” (22.8%, 16.5%). The classes were reasonably or very well separated, with the exception of walking in females. Latent class analysis was found to be a useful tool for characterizing longitudinal patterns of physical activity, even when the measurement instrument differs slightly across ages, which added value in comparison with observed activity at a single age.

Antenatal blood pressure for prediction of pre-eclampsia, preterm birth, and small for gestational age babies: development and validation in two general population cohorts

Study question Can routine antenatal blood pressure measurements between 20 and 36 weeks’ gestation contribute to the prediction of pre-eclampsia and its associated adverse outcomes? Methods This study used repeated antenatal measurements of blood pressure from 12 996 women in the Avon Longitudinal Study of Parents and Children (ALSPAC) to develop prediction models and validated these in 3005 women from the Southampton Women’s Survey (SWS). A model based on maternal early pregnancy characteristics only (BMI, height, age, parity, smoking, existing and previous gestational hypertension and diabetes, and ethnicity) plus initial mean arterial pressure was compared with a model additionally including current mean arterial pressure, a model including the deviation of current mean arterial pressure from a stratified normogram, and a model including both at different gestational ages from 20-36 weeks. Study answer and limitations The addition of blood pressure measurements from 28 weeks onwards improved prediction models compared with use of early pregnancy risk factors alone, but they contributed little to the prediction of preterm birth or small for gestational age. Though multiple imputation of missing data was used to increase the sample size and minimise selection bias, the validation sample might have been slightly underpowered as the number of cases of pre-eclampsia was just below the recommended 100. Several risk factors were self reported, potentially introducing measurement error, but this reflects how information would be obtained in clinical practice. What this study adds The addition of routinely collected blood pressure measurements from 28 weeks onwards improves predictive models for pre-eclampsia based on blood pressure in early pregnancy and other characteristics, facilitating a reduction in scheduled antenatal care. Funding, competing interests, data sharing UK Wellcome Trust, US National Institutes of Health, and UK Medical Research Council. Other funding sources for authors are detailed in the full online paper. With the exceptions of CM-W, HMI, and KMG there were no competing interests.

Early-life overweight trajectory and CKD in the 1946 British birth cohort study

Background Few studies have examined the impact of childhood obesity on later kidney disease, and consequently, our understanding is very limited. Study Design Longitudinal population-based cohort. Setting & Participants The Medical Research Council National Survey of Health and Development, a socially stratified sample of 5,362 singletons born in 1 week in March 1946 in England, Scotland, and Wales, of which 4,340 were analyzed. Predictor Early-life overweight latent classes (never, prepubertal only, pubertal onset, or always), derived from repeated measurements of body mass index between ages 2 and 20 years. Outcomes & Measurements The primary outcome was chronic kidney disease (CKD), defined as creatinine- or cystatin C–based estimated glomerular filtration rate (eGFRcr and eGFRcys, respectively) <60 mL/min/1.73 m2 or urine albumin-creatinine ratio (UACR) ≥3.5 mg/mmol measured at age 60-64 years. Associations were explored through regression analysis, with adjustment for socioeconomic position, smoking, physical activity level, diabetes, hypertension, and overweight at ages 36 and 53 years. Results 2.3% of study participants had eGFRcr <60 mL/min/1.73 m2, 1.7% had eGFRcys <60 mL/min/1.73 m2, and 2.9% had UACR ≥3.5 mg/mmol. Relative to being in the never-overweight latent class, being in the pubertal-onset– or always-overweight latent classes was associated with eGFRcys-defined CKD (OR, 2.04; 95% CI, 1.09-3.82). Associations with CKD defined by eGFRcr (OR, 1.27; 95% CI, 0.71-2.29) and UACR (OR, 1.33; 95% CI, 0.70-2.54) were less marked, but in the same direction. Adjustment for lifestyle and health factors had little impact on effect estimates. Limitations A low prevalence of CKD resulted in low statistical power. No documentation of chronicity for outcomes. All-white study population restricts generalizability. Conclusions Being overweight in early life was found to be associated with eGFRcys-defined CKD in later life. The associations with CKD defined by eGFRcr and UACR were less marked, but in the same direction. Reducing or preventing overweight in the early years of life may significantly reduce the burden of CKD in the population.

Associations of blood pressure in pregnancy with offspring blood pressure trajectories during childhood and adolescence: findings from a prospective study.

Background Hypertensive disorders of pregnancy are related to higher offspring blood pressure (BP), but it is not known whether this association strengthens or weakens as BP changes across childhood. Our aim was to assess the associations of hypertensive disorders of pregnancy and maternal BP changes during pregnancy with trajectories of offspring BP from age 7 to 18 years. Methods and Results In a large UK cohort of maternal–offspring pairs (N=6619), we used routine antenatal BP measurements to derive hypertensive disorders of pregnancy and maternal BP trajectories. These were related to offspring BP trajectories, obtained from research clinic assessments, using linear spline random-effects models. After adjusting for maternal and offspring variables, including body mass index, offspring of women who had existing hypertension, gestational hypertension, or preeclampsia during pregnancy had on average higher BP at age 7 years compared to offspring of normotensive pregnancies (mean difference [95%CI] in systolic BP: 1.67 mm Hg [0.48, 2.86], 1.98 mm Hg [1.32, 2.65], and 1.22 mm Hg [−0.52, 2.97], respectively). These differences were consistent across childhood to age 18 years, as the patterns of BP change did not differ between offspring of hypertensive pregnancies and normotensive pregnancies. Maternal BP at 8 weeks’ gestation was also positively associated with offspring BP in childhood and adolescence, but changes in BP across pregnancy were not strongly associated. Conclusions The differences in BP between offspring of hypertensive pregnancies and offspring of normotensive pregnancies remain consistent across childhood and adolescence. These associations appear to be most contributed to by higher maternal BP in early pregnancy rather than by pregnancy-related BP changes.