A discussion of statistical methods to characterise early growth and its impact on bone mineral content later in childhood.

BACKGROUND: Many statistical methods are available to model longitudinal growth data and relate derived summary measures to later outcomes. AIM: To apply and compare commonly used methods to a realistic scenario including pre- and postnatal data, missing data, and confounders. SUBJECTS AND METHODS: Data were collected from 753 offspring in the Southampton Women's Survey with measurements of bone mineral content (BMC) at age 6 years. Ultrasound measures included crown-rump length (11 weeks' gestation) and femur length (19 and 34 weeks' gestation); postnatally, infant length (birth, 6 and 12 months) and height (2 and 3 years) were measured. A residual growth model, two-stage multilevel linear spline model, joint multilevel linear spline model, SITAR and a growth mixture model were used to relate growth to 6-year BMC. RESULTS: Results from the residual growth, two-stage and joint multilevel linear spline models were most comparable: an increase in length at all ages was positively associated with BMC, the strongest association being with later growth. Both SITAR and the growth mixture model demonstrated that length was positively associated with BMC. CONCLUSIONS: Similarities and differences in results from a variety of analytic strategies need to be understood in the context of each statistical methodology.

Does pregnancy alter life-course lipid trajectories? Evidence from the HUNT Study in Norway.

We examined the association between pregnancy and life-course lipid trajectories. Linked data from the Nord-Trøndelag Health Study and the Medical Birth Registry of Norway yielded 19,987 parous and 1,625 nulliparous women. Using mixed-effects spline models, we estimated differences in nonfasting lipid levels from before to after first birth in parous women and between parous and nulliparous women. HDL cholesterol (HDL-C) dropped by -4.2 mg/dl (95% CI: -5.0, -3.3) from before to after first birth in adjusted models, a 7% change, and the total cholesterol (TC) to HDL-C ratio increased by 0.18 (95% CI: 0.11, 0.25), with no change in non-HDL-C or triglycerides. Changes in HDL-C and the TC/HDL-C ratio associated with pregnancy persisted for decades, leading to altered life-course lipid trajectories. For example, parous women had a lower HDL-C than nulliparous women at the age of 50 years (-1.4 mg/dl; 95% CI: -2.3, -0.4). Adverse changes in lipids were greatest after first birth, with small changes after subsequent births, and were larger in women who did not breastfeed. Findings suggest that pregnancy is associated with long-lasting adverse changes in HDL-C, potentially setting parous women on a more atherogenic trajectory than prior to pregnancy.

Derivative estimation for longitudinal data analysis: Examining features of blood pressure measured repeatedly during pregnancy.

Estimating velocity and acceleration trajectories allows novel inferences in the field of longitudinal data analysis, such as estimating change regions rather than change points, and testing group effects on nonlinear change in an outcome (ie, a nonlinear interaction). In this article, we develop derivative estimation for 2 standard approaches-polynomial mixed models and spline mixed models. We compare their performance with an established method-principal component analysis through conditional expectation through a simulation study. We then apply the methods to repeated blood pressure (BP) measurements in a UK cohort of pregnant women, where the goals of analysis are to (i) identify and estimate regions of BP change for each individual and (ii) investigate the association between parity and BP change at the population level. The penalized spline mixed model had the lowest bias in our simulation study, and we identified evidence for BP change regions in over 75% of pregnant women. Using mean velocity difference revealed differences in BP change between women in their first pregnancy compared with those who had at least 1 previous pregnancy. We recommend the use of penalized spline mixed models for derivative estimation in longitudinal data analysis.

Correction to: The impact of parity on life course blood pressure trajectories: the HUNT study in Norway.

The article was originally published electronically on the publisher's internet portal (currently SpringerLink) on 24 January 2018 without open access.

The impact of parity on life course blood pressure trajectories: the HUNT study in Norway.

The drop in blood pressure during pregnancy may persist postpartum, but the impact of pregnancy on blood pressure across the life course is not known. In this study we examined blood pressure trajectories for women in the years preceding and following pregnancy and compared life course trajectories of blood pressure for parous and nulliparous women. We linked information on all women who participated in the population-based, longitudinal HUNT Study, Norway with pregnancy information from the Medical Birth Registry of Norway. A total of 23,438 women were included with up to 3 blood pressure measurements per woman. Blood pressure trajectories were compared using a mixed effects linear spline model. Before first pregnancy, women who later gave birth had similar mean blood pressure to women who never gave birth. Women who delivered experienced a drop after their first birth of - 3.32 mmHg (95% CI, - 3.93, - 2.71) and - 1.98 mmHg (95% CI, - 2.43, - 1.53) in systolic and diastolic blood pressure, respectively. Subsequent pregnancies were associated with smaller reductions. These pregnancy-related reductions in blood pressure led to persistent differences in mean blood pressure, and at age 50, parous women still had lower systolic (- 1.93 mmHg; 95% CI, - 3.33, - 0.53) and diastolic (- 1.36 mmHg; 95% CI, - 2.26, - 0.46) blood pressure compared to nulliparous women. The findings suggest that the first pregnancy and, to a lesser extent, successive pregnancies are associated with lasting and clinically relevant reductions in systolic and diastolic blood pressure.

Association of parents' and children's physical activity and sedentary time in Year 4 (8-9) and change between Year 1 (5-6) and Year 4: a longitudinal study.

BACKGROUND: Parents could be important influences on child physical activity and parents are often encouraged to be more active with their child. This paper examined the association between parent and child physical activity and sedentary time in a UK cohort of children assessed when the children were in Year 1 (5-6 years old) and in Year 4 (8-9 years old). METHODS: One thousand two hundred twenty three children and parents provided data in Year 4 and of these 685 participated in Year 1. Children and parents wore an accelerometer for five days including a weekend. Mean minutes of sedentary time and moderate-to-vigorous intensity physical activity (MVPA) were derived. Multiple imputation was used to impute all missing data and create complete datasets. Linear regression models examined whether parent MVPA and sedentary time at Year 4 and at Year 1 predicted child MVPA and sedentary time at Year 4. Change in parent MVPA and sedentary time was used to predict change in child MVPA and sedentary time between Year 1 and Year 4. RESULTS: Imputed data showed that at Year 4, female parent sedentary time was associated with child sedentary time (0.13, 95% CI = 0.00 to 0.27 mins/day), with a similar association for male parents (0.15, 95% CI = -0.02 to 0.32 mins/day). Female parent and child MVPA at Year 4 were associated (0.16, 95% CI = 0.08 to 0.23 mins/day) with a smaller association for male parents (0.08, 95% CI = -0.01 to 0.17 mins/day). There was little evidence that either male or female parent MVPA at Year 1 predicted child MVPA at Year 4 with similar associations for sedentary time. There was little evidence that change in parent MVPA or sedentary time predicted change in child MVPA or sedentary time respectively. CONCLUSIONS: Parents who were more physically active when their child was 8-9 years old had a child who was more active, but the magnitude of association was generally small. There was little evidence that parental activity from three years earlier predicted child activity at age 8-9, or that change in parent activity predicted change in child activity.

Change in children's physical activity and sedentary time between Year 1 and Year 4 of primary school in the B-PROACT1V cohort.

BACKGROUND: The aim of this study was to examine how children's and parents' physical activity changes from Year 1 (5-6) to Year 4 (8-9 years of age). METHODS: Data are from the Bristol (UK) B-PROACT1V cohort. Fifty-seven primary schools were recruited when the children were in Year 1, with 1299 children and their parents providing data. Forty-seven schools were re-recruited in Year 4, with 1223 children and parents providing data (685 of whom participated in Year 1). Children and at least one parent wore an accelerometer for 5 days including a weekend and mean minutes of sedentary time, moderate-to-vigorous intensity physical activity (MVPA) and accelerometer counts per minute (CPM) were derived. Multiple imputation was used to impute missing data for all 1837 families who took part, including those who participated at just one time. Paired t-tests examined if there was statistical evidence of change in accelerometer measures. RESULTS: Multiple imputation and observed data were comparable and results using complete observed data were mostly the same as those using imputed data. Imputed data showed that mean boys' CPM decreased from 747 to 673 (difference in mean 74 [95% CI 45 to 103]) and girls' from 686 to 587 (99 [79 to 119]). Boys' time spent in MVPA reduced from 72 to 69 (3 [0 to 6]) and girls' from 62 to 56 (7 [4 to 9]) minutes per day. There were increases in sedentary time for both boys (354 to 428 min, 74 [61 to 88]) and girls (365 to 448, 83 [71 to 96]). There was no evidence of change in parent CPM or MVPA. Mothers' sedentary time increased by 26 min per day [16 to 35]. CONCLUSIONS: There were similar increases in sedentary time in girls and boys between age 5-6 and 8-9, and decreases in MVPA that were more marked in girls. The similarity of multiple-imputed and complete observed data suggest that these findings may not be markedly affected by selection bias. Result support early interventions to prevent the age-related decline in children's physical activity.

Hypertensive disorders of pregnancy, respiratory outcomes and atopy in childhood.

Few epidemiological studies have investigated the role of hypertensive disorders of pregnancy in the aetiology of childhood respiratory and atopic outcomes.In the Avon Longitudinal Study of Parents and Children we examined associations of maternal gestational hypertension, hypertension before pregnancy and pre-eclampsia with wheezing at 18 months, wheezing and asthma at 7 years and lung function at 8-9 years, after controlling for potential confounders (n=5322-8734, depending on outcome).Gestational hypertension was not associated with any of the outcomes. There was weak evidence for a positive association between pre-eclampsia and early wheezing (adjusted OR 1.31, 95% CI 0.94-1.82, compared to normotensive pregnancies) and for negative associations between pre-eclampsia and forced expiratory volume in 1 s (adjusted mean difference in sd score -0.14, 95% CI -0.33-0.06) and maximal mid-expiratory flow (-0.15, 95% CI -0.34-0.04). Hypertension before pregnancy was positively associated with wheezing (OR 1.63, 95% CI 1.16-2.31) and asthma (OR 1.34, 95% CI 1.00-1.79).Gestational hypertension is unlikely to be a risk factor for childhood respiratory disorders; hypertension before pregnancy may be a risk factor for childhood wheezing and asthma, but this finding needs replication. Larger studies are needed to confirm whether pre-eclampsia is associated with impaired childhood lung function.

Association of maternal diabetes/glycosuria and pre-pregnancy body mass index with offspring indicators of non-alcoholic fatty liver disease.

BACKGROUND: Little is known about early life determinants of non-alcoholic fatty liver disease (NAFLD). We examined associations of maternal pregnancy diabetes/glycosuria and pre-pregnancy body mass index (BMI) with offspring markers of NAFLD and liver pathology and examined mediation by birthweight and concurrent offspring adiposity. METHODS: We used data from a UK prospective pregnancy cohort. Offspring underwent abdominal ultrasonography (USS) at mean age 17.8 years. Outcomes included USS-assessed fatty liver, estimated liver volume and shear velocity, a variant of elastography (a marker of liver fibrosis) (N = 1 215) and blood-based markers of liver pathology [alanine amino transferase, aspartate amino transferase, gamma- glutamyltransferase and haptoglobin] (N = 2 359). RESULTS: 2.1 % (N = 25) of participants had USS-assessed fatty liver [maternal diabetes/glycosuria (N = 7) and no diabetes/glycosuria (N = 18)]. Maternal diabetes/glycosuria was associated with greater odds of offspring USS fatty liver in confounder adjusted models [adjusted odds ratio (aOR) 6.74 (95 % confidence interval (CI) 2.47, 18.40)] and higher shear velocity [adjusted ratio of geometric mean (aRGM):1.10 (95 % CI 1.05, 1.15)]. These associations were not mediated by offspring birthweight or concurrent adiposity. Maternal diabetes/glycosuria was not associated with liver volume or blood-based outcomes. Greater maternal pre-pregnancy BMI was associated with greater odds of offspring USS fatty liver [aOR 2.72 (95 % CI: 1.20, 6.15)], higher liver volume [aRGM 1.03 (95 % CI 1.00, 1.07)] and shear velocity [aRGM1.03 (95 % CI: 1.01, 1.06)] in confounder adjusted models. These associations were largely mediated by offspring adiposity. Maternal pre-pregnancy BMI was not consistently associated with blood-based outcomes. CONCLUSIONS: Results suggest that maternal pregnancy diabetes/glycosuria is associated with offspring NAFLD through mechanisms other than offspring's own adiposity.

Plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study.

OBJECTIVE: To investigate the role of longitudinal plasma neurofilament heavy chain protein (NfH) levels as an indicator of clinical progression and survival in amyotrophic lateral sclerosis (ALS). METHODS: A cross-sectional study involving 136 clinically heterogeneous patients with ALS and 104 healthy and neurological controls was extended to include a prospective analysis of 74 of these ALS cases, with samplings at approximately 3-month intervals in a follow-up period of up to 3 years. We analysed the correlation between longitudinal NfH-phosphoform levels and disease progression. Temporal patterns of NfH changes were evaluated using multilevel linear regression. RESULTS: Baseline plasma NfH levels were higher than controls only in patients with ALS with short disease duration to baseline sampling. Compared with controls, fast-progressing patients with ALS, particularly those with a short diagnostic latency and disease duration, had higher plasma NfH levels at an early stage and lower levels closer to end-stage disease. Lower NfH levels between visits were associated with rapid functional deterioration. We also detected antibodies against NfH, NfH aggregates and NfH cleavage products. CONCLUSIONS: Disease progression in ALS involves defined trajectories of plasma NfH levels, reflecting speed of neurological decline and survival. Intervisit plasma NfH changes are also indicative of disease progression. This study confirms that longitudinal measurements of NfH plasma levels are more informative than cross-sectional studies, where the time of sampling may represent a bias in the interpretation of the results. Autoantibodies against NfH aggregates and NfH cleavage products may explain the variable expression of plasma NfH with disease progression. TRAIL REGISTRATION NUMBER: NIHRID6160.

Childhood energy intake is associated with nonalcoholic fatty liver disease in adolescents.

BACKGROUND: Greater adiposity is an important risk factor for nonalcoholic fatty liver disease (NAFLD). Thus, it is likely that dietary intake is involved in the development of the disease. Prospective studies assessing the relation between childhood dietary intake and risk of NAFLD are lacking. OBJECTIVE: This study was designed to explore associations between energy, carbohydrate, sugar, starch, protein, monounsaturated fat, polyunsaturated fat, saturated fat, and total fat intake by youth at ages 3, 7, and 13 y and subsequent (mean age: 17.8 y) ultrasound scan (USS)-measured liver fat and stiffness and serum alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase. We assessed whether observed associations were mediated through fat mass at the time of outcome assessment. METHODS: Participants were from the Avon Longitudinal Study of Parents and Children. Trajectories of energy and macronutrient intake from ages 3-13 y were obtained with linear-spline multilevel models. Linear and logistic regression models examined whether energy intake and absolute and energy-adjusted macronutrient intake at ages 3, 7, and 13 y were associated with liver outcomes. RESULTS: Energy intake at all ages was positively associated with liver outcomes; for example, the odds of having a USS-measured liver fat per 100 kcal increase in energy intake at age 3 y were 1.79 (95% CI: 1.14, 2.79). Associations between absolute macronutrient intake and liver outcomes were inconsistent and attenuated to the null after adjustment for total energy intake. The majority of associations attenuated to the null after adjustment for fat mass at the time liver outcomes were assessed. CONCLUSION: Higher childhood and early adolescent energy intake is associated with greater NAFLD risk, and the macronutrients from which energy intake is derived are less important. These associations appear to be mediated, at least in part, by fat mass at the time of outcome assessment.

Association between pre- and perinatal exposures and Tourette syndrome or chronic tic disorder in the ALSPAC cohort.

BACKGROUND: Tourette syndrome and chronic tic disorder are heritable but aetiologically complex. Although environment plays a role in their development, existing studies of non-genetic risk factors are inconsistent. AIMS: To examine the association between pre- and perinatal exposures and Tourette syndrome/chronic tic disorder in the Avon Longitudinal Study of Parents and Children (ALSPAC) prospective longitudinal pre-birth cohort. METHOD: Relationships between exposures and Tourette syndrome/chronic tic disorder were examined in 6090 children using logistic regression. RESULTS: Maternal alcohol and cannabis use, inadequate maternal weight gain and parity were associated with Tourette syndrome or Tourette syndrome/chronic tic disorder. Other previously reported exposures, including birth weight and prenatal maternal smoking, were not associated with Tourette syndrome/chronic tic disorder. CONCLUSIONS: This study supports previously reported relationships between Tourette syndrome/chronic tic disorder and prenatal alcohol exposure, and identifies additional previously unexplored potential prenatal risk factors.

Modelling childhood growth using fractional polynomials and linear splines.

BACKGROUND: There is increasing emphasis in medical research on modelling growth across the life course and identifying factors associated with growth. Here, we demonstrate multilevel models for childhood growth either as a smooth function (using fractional polynomials) or a set of connected linear phases (using linear splines). METHODS: We related parental social class to height from birth to 10 years of age in 5,588 girls from the Avon Longitudinal Study of Parents and Children (ALSPAC). Multilevel fractional polynomial modelling identified the best-fitting model as being of degree 2 with powers of the square root of age, and the square root of age multiplied by the log of age. The multilevel linear spline model identified knot points at 3, 12 and 36 months of age. RESULTS: Both the fractional polynomial and linear spline models show an initially fast rate of growth, which slowed over time. Both models also showed that there was a disparity in length between manual and non-manual social class infants at birth, which decreased in magnitude until approximately 1 year of age and then increased. CONCLUSIONS: Multilevel fractional polynomials give a more realistic smooth function, and linear spline models are easily interpretable. Each can be used to summarise individual growth trajectories and their relationships with individual-level exposures.

Associations of pregnancy complications with calculated cardiovascular disease risk and cardiovascular risk factors in middle age: the Avon Longitudinal Study of Parents and Children.

BACKGROUND: The nature and contribution of different pregnancy-related complications to future cardiovascular disease (CVD) and its risk factors and the mechanisms underlying these associations remain unclear. METHODS AND RESULTS: We studied associations of pregnancy diabetes mellitus, hypertensive disorders of pregnancy, preterm delivery, and size for gestational age with calculated 10-year CVD risk (based on the Framingham score) and a wide range of cardiovascular risk factors measured 18 years after pregnancy (mean age at outcome assessment, 48 years) in a prospective cohort of 3416 women. Gestational diabetes mellitus was positively associated with fasting glucose and insulin, even after adjustment for potential confounders, whereas hypertensive disorders of pregnancy were associated with body mass index, waist circumference, blood pressure, lipids, and insulin. Large for gestational age was associated with greater waist circumference and glucose concentrations, whereas small for gestational age and preterm delivery were associated with higher blood pressure. The association with the calculated 10-year CVD risk based on the Framingham prediction score was odds ratio 1.31 (95 confidence interval, 1.11-1.53) for preeclampsia and 1.26 (95 confidence interval, 0.95-1.68) for gestational diabetes mellitus compared with women without preeclampsia and without gestational diabetes mellitus, respectively. CONCLUSIONS: Hypertensive disorders of pregnancy and pregnancy diabetes mellitus are independently associated with an increased calculated 10-year CVD risk. Preeclampsia may be the better predictor of future CVD because it was associated with a wider range of cardiovascular risk factors. Our results suggest that pregnancy may be an important opportunity for early identification of women at increased risk of CVD later in life.

Estimating trajectories of energy intake through childhood and adolescence using linear-spline multilevel models.

BACKGROUND: Methods for the assessment of changes in dietary intake across the life course are underdeveloped. METHODS: We demonstrate the use of linear-spline multilevel models to summarize energy-intake trajectories through childhood and adolescence and their application as exposures, outcomes, or mediators. The Avon Longitudinal Study of Parents and Children assessed children's dietary intake several times between ages 3 and 13 years, using both food frequency questionnaires (FFQs) and 3-day food diaries. We estimated energy-intake trajectories for 12,032 children using linear-spline multilevel models. We then assessed the associations of these trajectories with maternal body mass index (BMI), and later offspring BMI, and also their role in mediating the relation between maternal and offspring BMIs. RESULTS: Models estimated average and individual energy intake at 3 years, and linear changes in energy intake from age 3 to 7 years and from age 7 to 13 years. By including the exposure (in this example, maternal BMI) in the multilevel model, we were able to estimate the average energy-intake trajectories across levels of the exposure. When energy-intake trajectories are the exposure for a later outcome (in this case offspring BMI) or a mediator (between maternal and offspring BMI), results were similar, whether using a two-step process (exporting individual-level intercepts and slopes from multilevel models and using these in linear regression/path analysis), or a single-step process (multivariate multilevel models). Trajectories were similar when FFQs and food diaries were assessed either separately, or when combined into one model. CONCLUSIONS: Linear-spline multilevel models provide useful summaries of trajectories of dietary intake that can be used as an exposure, outcome, or mediator.

Gestational weight gain as a risk factor for hypertensive disorders of pregnancy.

OBJECTIVE: Pregnancy interventions to limit gestational weight gain (GWG) have been proposed as a means of preventing hypertensive disorders of pregnancy (HDP); however, it is currently unclear whether GWG has a causal influence on the development of HDP. Thus, we aimed to determine whether GWG in early pregnancy is a risk factor for preeclampsia and gestational hypertension and whether GWG precedes the increases in blood pressure in normotensive women across pregnancy. STUDY DESIGN: We examined repeat antenatal clinic measurements of weight and blood pressure (median of 12 and 14 per woman, respectively) of 12,522 women in the Avon Longitudinal Study of Parents and Children. RESULTS: Greater prepregnancy weight was associated with an increased risk of gestational hypertension and preeclampsia per 10 kg of prepregnancy weight: odds ratio (OR), 1.80; 95% confidence interval (CI), 1.70-1.91 and OR, 1.71; 95% CI, 1.49-1.95, respectively, for women weighing 90 kg or less before pregnancy; OR, 1.24; 95% CI, 1.03-1.49 and OR, 1.61; 95% CI, 1.18-2.19 for women weighing more than 90 kg. Fully adjusted odds ratios for gestational hypertension and preeclampsia per 200 g per week GWG up to 18 weeks were OR, 1.26; 95% CI, 1.16-1.38 and OR, 1.31; 95% CI, 1.07-1.62. In normotensive women, GWG in early pregnancy was associated positively with blood pressure change in midpregnancy and negatively with blood pressure change in late pregnancy. In all gestational periods, GWG was positively associated with concurrent blood pressure change. However, there was no evidence that blood pressure changes in any period were associated with subsequent GWG. CONCLUSION: These findings suggest that GWG in early pregnancy may be a potential target for interventions aimed at reducing the risk of HDP.

Cardiovascular biomarkers and vascular function during childhood in the offspring of mothers with hypertensive disorders of pregnancy: findings from the Avon Longitudinal Study of Parents and Children.

AIMS: It is uncertain if the higher blood pressure (BP) observed in the offspring of hypertensive pregnancies is an isolated abnormality or one that is accompanied by impaired vascular function and alterations in lipid and inflammation markers that would be indicative of a more general cardiometabolic disturbance of the type observed in the mother during pre-eclampsia. METHODS AND RESULTS: In a large UK cohort of maternal-offspring pairs (n = 3537-4654), assessed at age 9-12 years, we examined the associations of maternal gestational hypertension and pre-eclampsia with offspring BP, endothelial function assessed by brachial artery flow-mediated dilatation; arterial stiffness assessed by carotid to radial pulse wave velocity; brachial artery distensibility and BP (vascular outcomes); as well as markers of inflammation, lipids and apolipoproteins A1 and B. Offspring of women with pre-eclampsia or gestational hypertension had higher systolic blood pressure by 2.04 mmHg (95% CI: 1.33, 2.76) and 1.82 mmHg (95% CI: 0.03, 3.62), respectively, and higher diastolic blood pressure by 1.10 mmHg (95% CI: 0.47, 1.73) and 1.26 mmHg (95% CI: -0.32, 2.85), respectively, in analyses adjusted for maternal and offspring body mass index (BMI), offspring dietary sodium intake and other potential confounders. However, we found no associations of either hypertensive disorder of pregnancy with the other vascular outcomes or with inflammatory markers, lipids, and apolipoproteins. CONCLUSION: Pre-eclampsia and gestational hypertension are associated with higher offspring BP in childhood in the absence of other vascular alterations or metabolic derangements. The findings support the existence of shared mother-offspring risk factors that are specific for higher BP, rather than the additional cardiometabolic abnormalities of hypertensive disorder of pregnancy having long-term consequences for offspring.

Multivariate multilevel spline models for parallel growth processes: application to weight and mean arterial pressure in pregnancy.

Growth models are commonly used in life course epidemiology to describe growth trajectories and their determinants or to relate particular patterns of change to later health outcomes. However, methods to analyse relationships between two or more change processes occurring in parallel, in particular to assess evidence for causal influences of change in one variable on subsequent changes in another, are less developed. We discuss linear spline multilevel models with a multivariate response and show how these can be used to relate rates of change in a particular time period in one variable to later rates of change in another variable by using the variances and covariances of individual-level random effects for each of the splines. We describe how regression coefficients can be calculated for these associations and how these can be adjusted for other parameters such as random effect variables relating to baseline values or rates of change in earlier time periods, and compare different methods for calculating the standard errors of these regression coefficients. We also show that these models can equivalently be fitted in the structural equation modelling framework and apply each method to weight and mean arterial pressure changes during pregnancy, obtaining similar results for multilevel and structural equation models. This method improves on the multivariate linear growth models, which have been used previously to model parallel processes because it enables nonlinear patterns of change to be modelled and the temporal sequence of multivariate changes to be determined, with adjustment for change in earlier time periods.

Associations between grip strength of parents and their 4-year-old children: findings from the Southampton Women's Survey.

Relationships between birthweight and grip strength throughout the life course suggest that early influences on the growth and development of muscle are important for long-term muscle function. However, little is known about parental influences on children's grip strength. We have explored this in the Southampton Women's Survey, a prospective general population cohort study from before conception through childhood. Grip strength was measured using a Jamar handgrip dynamometer in the mother at 19 weeks' gestation and her partner, and in the child at age 4 years. Pre-pregnancy heights and weights were measured in the mothers; reported weights and measured heights were available for the fathers. Complete data on parents and children were available for 444 trios. In univariable analyses, both parents' grip strengths were significantly associated with that of the child (r = 0.17, P < 0.001 for mothers; r = 0.15, P = 0.002 for fathers). These correlations were similar to that between the grip strength of the mothers and the fathers (r = 0.17, P < 0.001). In the multivariable model, after adjustment for child's height and physical activity, the correlations with the child's grip strength were attenuated, being 0.10 (P = 0.02) and 0.11 (P = 0.01) for mothers' and fathers' grip strength respectively. The findings show that grip strength of each parent is associated with that of the child, indicating that heritable influences and the shared family environment influence the development of muscle strength. This contributes to our understanding of the role of heritable and environmental factors on early muscle growth and development, which are important for muscle function across the life course.

Predicting Early Allograft Function After Normothermic Machine Perfusion.

BACKGROUND: Normothermic ex situ liver perfusion is increasingly used to assess donor livers, but there remains a paucity of evidence regarding criteria upon which to base a viability assessment or criteria predicting early allograft function. METHODS: Perfusate variables from livers undergoing normothermic ex situ liver perfusion were analyzed to see which best predicted the Model for Early Allograft Function score. RESULTS: One hundred fifty-four of 203 perfused livers were transplanted following our previously defined criteria. These comprised 84/123 donation after circulatory death livers and 70/80 donation after brain death livers. Multivariable analysis suggested that 2-h alanine transaminase, 2-h lactate, 11 to 29 mmol supplementary bicarbonate in the first 4 h, and peak bile pH were associated with early allograft function as defined by the Model for Early Allograft Function score. Nonanastomotic biliary strictures occurred in 11% of transplants, predominantly affected first- and second-order ducts, despite selection based on bile glucose and pH. CONCLUSIONS: This work confirms the importance of perfusate alanine transaminase and lactate at 2-h, as well as the amount of supplementary bicarbonate required to keep the perfusate pH > 7.2, in the assessment of livers undergoing perfusion. It cautions against the use of lactate as a sole indicator of viability and also suggests a role for cholangiocyte function markers in predicting early allograft function.