Categorisation of continuous covariates for stratified randomisation: How should we adjust?

To obtain valid inference following stratified randomisation, treatment effects should be estimated with adjustment for stratification variables. Stratification sometimes requires categorisation of a continuous prognostic variable (eg, age), which raises the question: should adjustment be based on randomisation categories or underlying continuous values? In practice, adjustment for randomisation categories is more common. We reviewed trials published in general medical journals and found none of the 32 trials that stratified randomisation based on a continuous variable adjusted for continuous values in the primary analysis. Using data simulation, this article evaluates the performance of different adjustment strategies for continuous and binary outcomes where the covariate-outcome relationship (via the link function) was either linear or non-linear. Given the utility of covariate adjustment for addressing missing data, we also considered settings with complete or missing outcome data. Analysis methods included linear or logistic regression with no adjustment for the stratification variable, adjustment for randomisation categories, or adjustment for continuous values assuming a linear covariate-outcome relationship or allowing for non-linearity using fractional polynomials or restricted cubic splines. Unadjusted analysis performed poorly throughout. Adjustment approaches that misspecified the underlying covariate-outcome relationship were less powerful and, alarmingly, biased in settings where the stratification variable predicted missing outcome data. Adjustment for randomisation categories tends to involve the highest degree of misspecification, and so should be avoided in practice. To guard against misspecification, we recommend use of flexible approaches such as fractional polynomials and restricted cubic splines when adjusting for continuous stratification variables in randomised trials.

Association of cord blood vitamin D with child neurodevelopment at 7 years of age.

AIM: The role of fetal vitamin D [25-hydroxyvitamin D (25(OH)D)], one of the nuclear steroid transcription regulators, and brain development is unclear. We previously found a weak but persistent association between cord blood 25(OH)D and child language abilities at 18 months and 4 years of age, but no association with cognition or behaviour. The aim of this study was to investigate the association between cord blood 25(OH)D and a range of neurodevelopmental outcomes in these same children at 7 years of age. METHODS: Cord blood samples from 250 Australian mother-child pairs were analysed for 25(OH)D by mass spectroscopy. Children underwent tests of cognition, language, academic abilities and executive functions with a trained assessor at 7 years of age. Caregivers completed questionnaires to rate their child's behaviour and executive functioning in the home environment. Associations between standardised 25(OH)D and outcomes were assessed using regression models, taking into account possible social and demographic confounders. RESULTS: Standardised 25(OH)D in cord blood was not associated with any test or parent-rated scores. Nor was there any association with the risk of having a poor test or parent-rated score. Likewise, cord blood 25(OH)D categorised as <25, 25-50 and >50 nmol/L was not associated with test scores or parent-rated scores. CONCLUSIONS: There was no evidence that cord blood vitamin D concentration or deficiency was associated with cognition, language, academic abilities, executive functioning or behaviour at 7 years of age.

Handling misclassified stratification variables in the analysis of randomised trials with continuous outcomes.

Many trials use stratified randomisation, where participants are randomised within strata defined by one or more baseline covariates. While it is important to adjust for stratification variables in the analysis, the appropriate method of adjustment is unclear when stratification variables are affected by misclassification and hence some participants are randomised in the incorrect stratum. We conducted a simulation study to compare methods of adjusting for stratification variables affected by misclassification in the analysis of continuous outcomes when all or only some stratification errors are discovered, and when the treatment effect or treatment-by-covariate interaction effect is of interest. The data were analysed using linear regression with no adjustment, adjustment for the strata used to perform the randomisation (randomisation strata), adjustment for the strata if all errors are corrected (true strata), and adjustment for the strata after some errors are discovered and corrected (updated strata). The unadjusted model performed poorly in all settings. Adjusting for the true strata was optimal, while the relative performance of adjusting for the randomisation strata or the updated strata varied depending on the setting. As the true strata are unlikely to be known with certainty in practice, we recommend using the updated strata for adjustment and performing subgroup analyses, provided the discovery of errors is unlikely to depend on treatment group, as expected in blinded trials. Greater transparency is needed in the reporting of stratification errors and how they were addressed in the analysis.

Partially clustered designs for clinical trials: Unifying existing designs using consistent terminology.

INTRODUCTION: Clinical trial designs based on the assumption of independent observations are well established. Clustered clinical trial designs, where all observational units belong to a cluster and outcomes within clusters are expected to be correlated, have also received considerable attention. However, many clinical trials involve partially clustered data, where only some observational units belong to a cluster. Examples of such trials occur in neonatology, where participants include infants from both singleton and multiple births, and ophthalmology, where one or two eyes per participant may need treatment. Partial clustering can also arise in trials of group-based treatments (e.g. group education or counselling sessions) or treatments administered individually by a discrete number of health care professionals (e.g. surgeons or physical therapists), when this is compared to an unclustered control arm. Trials involving partially clustered data have received limited attention in the literature and the current lack of standardised terminology may be hampering the development and dissemination of methods for designing and analysing these trials. METHODS AND EXAMPLES: In this article, we present an overarching definition of partially clustered trials, bringing together several existing trial designs including those for group-based treatments, clustering due to facilitator effects and the re-randomisation design. We define and describe four types of partially clustered trial designs, characterised by whether the clustering occurs pre-randomisation or post-randomisation and, in the case of pre-randomisation clustering, by the method of randomisation that is used for the clustered observations (individual randomisation, cluster randomisation or balanced randomisation within clusters). Real life examples are provided to highlight the occurrence of partially clustered trials across a variety of fields. To assess how partially clustered trials are currently reported, we review published reports of partially clustered trials. DISCUSSION: Our findings demonstrate that the description of these trials is often incomplete and the terminology used to describe the trial designs is inconsistent, restricting the ability to identify these trials in the literature. By adopting the definitions and terminology presented in this article, the reporting of partially clustered trials can be substantially improved, and we present several recommendations for reporting these trial designs in practice. Greater awareness of partially clustered trials will facilitate more methodological research into their design and analysis, ultimately improving the quality of these trials.

Multiple imputation for handling missing outcome data in randomized trials involving a mixture of independent and paired data.

Randomized trials involving independent and paired observations occur in many areas of health research, for example in paediatrics, where studies can include infants from both single and twin births. Multiple imputation (MI) is often used to address missing outcome data in randomized trials, yet its performance in trials with independent and paired observations, where design effects can be less than or greater than one, remains to be explored. Using simulated data and through application to a trial dataset, we investigated the performance of different methods of MI for a continuous or binary outcome when followed by analysis using generalized estimating equations to account for clustering due to the pairs. We found that imputing data separately for independent and paired data, with paired data imputed in wide format, was the best performing MI method, producing unbiased point and standard error estimates for the treatment effect throughout. Ignoring clustering in the imputation model performed well in settings where the design effect due to the inclusion of paired data was close to one, but otherwise led to moderately biased variance estimates. Including a random cluster effect in the imputation model led to slightly biased point estimates for binary outcome data and variance estimates that were too small in some settings. Based on these results, we recommend researchers impute independent and paired data separately where feasible to do so. The exception is if the design effect due to the inclusion of paired data is close to one, where ignoring clustering may be appropriate.

DHA supplementation in infants born preterm and the effect on attention at 18 months' corrected age: follow-up of a subset of the N3RO randomised controlled trial.

Infants born preterm miss out on the peak period of in utero DHA accretion to the brain during the last trimester of pregnancy which is hypothesised to contribute to the increased prevalence of neurodevelopmental deficits in this population. This study aimed to determine whether DHA supplementation in infants born preterm improves attention at 18 months' corrected age. This is a follow-up of a subset of infants who participated in the N3RO randomised controlled trial. Infants were randomised to receive an enteral emulsion of high-dose DHA (60 mg/kg per d) or no DHA (soya oil - control) from within the first days of birth until 36 weeks' post-menstrual age. The assessment of attention involved three tasks requiring the child to maintain attention on toy/s in either the presence or absence of competition or a distractor. The primary outcome was the child's latency of distractibility when attention was focused on a toy. The primary outcome was available for seventy-three of the 120 infants that were eligible to participate. There was no evidence of a difference between groups in the latency of distractibility (adjusted mean difference: 0·08 s, 95 % CI -0·81, 0·97; P = 0·86). Enteral DHA supplementation did not result in improved attention in infants born preterm at 18 months' corrected age.

Conducting Clinical Trials in Twin Populations: A Review of Design, Analysis, Recruitment and Ethical Issues for Twin-Only Trials.

Although twins often participate in medical research, few clinical trials are conducted entirely in twin populations. The purpose of this review is to demonstrate the substantial benefits and address the key challenges of conducting clinical trials in twin populations, or 'twin-only trials'. We consider the unique design, analysis, recruitment and ethical issues that arise in such trials. In particular, we describe the different approaches available for randomizing twin pairs, highlight the similarity or correlation that exists between outcomes of twins, and discuss the impact of this correlation on sample size calculations and statistical analysis methods for estimating treatment effects. We also consider the role of both monozygotic and dizygotic twins for studying variation in outcomes, the factors that may affect recruitment of twins, and the ethics of conducting trials entirely in twin populations. The advantages and disadvantages of conducting twin-only trials are also discussed. Finally, we recommend that twin-only trials should be considered more often.

Comparison of iodine status pre- and post-mandatory iodine fortification of bread in South Australia: a population study using newborn thyroid-stimulating hormone concentration as a marker.

OBJECTIVE: The present study aimed to evaluate the effect of mandatory iodine fortification of bread on the iodine status of South Australian populations using newborn thyroid-stimulating hormone (TSH) concentration as a marker. DESIGN: The study used an interrupted time-series design. SETTING: TSH data collected between 2005 and 2016 (n 211 033) were extracted from the routine newborn screening programme in South Australia for analysis. Iodine deficiency is indicated when more than 3 % of newborns have TSH > 5 mIU/l. PARTICIPANTS: Newborns were classified into three groups: the pre-fortification group (those born before October 2009); the transition group (born between October 2009 and June 2010); and the post-fortification group (born after June 2010). RESULTS: The percentage of newborns with TSH > 5 mIU/l was 5·1, 6·2 and 4·6 % in the pre-fortification, transition and post-fortification groups, respectively. Based on a segmented regression model, newborns in the post-fortification period had a 10 % lower risk of having TSH > 5 mIU/l than newborns in the pre-fortification group (incidence rate ratio (IRR) = 0·90; 95 % CI 0·87, 0·94), while newborns in the transitional period had a 22 % higher risk of having TSH > 5 mIU/l compared with newborns in the pre-fortification period (IRR = 1·22; 95 % CI 1·13, 1·31). CONCLUSIONS: Using TSH as a marker, South Australia would be classified as mild iodine deficiency post-fortification in contrast to iodine sufficiency using median urinary iodine concentration as a population marker. Re-evaluation of the current TSH criteria to define iodine status in populations is warranted in this context.

Effects of an antenatal dietary intervention in overweight and obese women on 6 month infant outcomes: follow-up from the LIMIT randomised trial.

BACKGROUND: The immediate impact of providing an antenatal dietary intervention during pregnancy has been extensively studied, but little is known of the effects beyond the neonatal period. Our objective was to evaluate the effect of an antenatal dietary intervention in overweight or obese women on infant outcomes 6 months after birth. METHODS: We conducted a follow up study of infants born to women who participated in the LIMIT trial during pregnancy. Live-born infants at 6-months of age, and whose mother provided consent to ongoing follow-up were eligible. The primary follow-up study endpoint was the incidence of infant BMI z-score ≥90th centile for infant sex and age. Secondary study outcomes included a range of infant anthropometric measures, neurodevelopment, general health, and infant feeding. Analyses used intention to treat principles according to the treatment group allocated in pregnancy. Missing data were imputed and analyses adjusted for maternal early pregnancy BMI, parity, study centre, socioeconomic status, age, and smoking status. Outcome assessors were blinded to the allocated treatment group. RESULTS: A total of 1754 infants were assessed at age 6 months (Lifestyle Advice n = 869; Standard Care n = 885), representing 82.1% of the eligible sample (n = 2136). There were no statistically significant differences in the incidence of infant BMI z-score ≥90th centile for infants born to women in the Lifestyle Advice group, compared with the Standard Care group (Lifestyle Advice 233 (21.71%) vs. Standard Care 233 (21.90%); adjusted relative risk (aRR) 0.99; 95% confidence interval 0.82 to 1.18; p = 0.88). There were no other effects on infant growth, adiposity, or neurodevelopment. CONCLUSION: Providing pregnant women who were overweight or obese with an antenatal dietary and lifestyle intervention did not alter 6-month infant growth and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry (ACTRN12607000161426).

Accounting for twin births in sample size calculations for randomised trials.

BACKGROUND: Including twins in randomised trials leads to non-independence or clustering in the data. Clustering has important implications for sample size calculations, yet few trials take this into account. Estimates of the intracluster correlation coefficient (ICC), or the correlation between outcomes of twins, are needed to assist with sample size planning. Our aims were to provide ICC estimates for infant outcomes, describe the information that must be specified in order to account for clustering due to twins in sample size calculations, and develop a simple tool for performing sample size calculations for trials including twins. METHODS: ICCs were estimated for infant outcomes collected in four randomised trials that included twins. The information required to account for clustering due to twins in sample size calculations is described. A tool that calculates the sample size based on this information was developed in Microsoft Excel and in R as a Shiny web app. RESULTS: ICC estimates ranged between -0.12, indicating a weak negative relationship, and 0.98, indicating a strong positive relationship between outcomes of twins. Example calculations illustrate how the ICC estimates and sample size calculator can be used to determine the target sample size for trials including twins. CONCLUSIONS: Clustering among outcomes measured on twins should be taken into account in sample size calculations to obtain the desired power. Our ICC estimates and sample size calculator will be useful for designing future trials that include twins. Publication of additional ICCs is needed to further assist with sample size planning for future trials.

Prevalence and reporting of recruitment, randomisation and treatment errors in clinical trials: A systematic review.

Background/aims In clinical trials, it is not unusual for errors to occur during the process of recruiting, randomising and providing treatment to participants. For example, an ineligible participant may inadvertently be randomised, a participant may be randomised in the incorrect stratum, a participant may be randomised multiple times when only a single randomisation is permitted or the incorrect treatment may inadvertently be issued to a participant at randomisation. Such errors have the potential to introduce bias into treatment effect estimates and affect the validity of the trial, yet there is little motivation for researchers to report these errors and it is unclear how often they occur. The aim of this study is to assess the prevalence of recruitment, randomisation and treatment errors and review current approaches for reporting these errors in trials published in leading medical journals. Methods We conducted a systematic review of individually randomised, phase III, randomised controlled trials published in New England Journal of Medicine, Lancet, Journal of the American Medical Association, Annals of Internal Medicine and British Medical Journal from January to March 2015. The number and type of recruitment, randomisation and treatment errors that were reported and how they were handled were recorded. The corresponding authors were contacted for a random sample of trials included in the review and asked to provide details on unreported errors that occurred during their trial. Results We identified 241 potentially eligible articles, of which 82 met the inclusion criteria and were included in the review. These trials involved a median of 24 centres and 650 participants, and 87% involved two treatment arms. Recruitment, randomisation or treatment errors were reported in 32 in 82 trials (39%) that had a median of eight errors. The most commonly reported error was ineligible participants inadvertently being randomised. No mention of recruitment, randomisation or treatment errors was found in the remaining 50 of 82 trials (61%). Based on responses from 9 of the 15 corresponding authors who were contacted regarding recruitment, randomisation and treatment errors, between 1% and 100% of the errors that occurred in their trials were reported in the trial publications. Conclusion Recruitment, randomisation and treatment errors are common in individually randomised, phase III trials published in leading medical journals, but reporting practices are inadequate and reporting standards are needed. We recommend researchers report all such errors that occurred during the trial and describe how they were handled in trial publications to improve transparency in reporting of clinical trials.

The effect of an antenatal lifestyle intervention in overweight and obese women on circulating cardiometabolic and inflammatory biomarkers: secondary analyses from the LIMIT randomised trial.

BACKGROUND: Maternal overweight and obesity during pregnancy is associated with insulin resistance, hyperglycaemia, hyperlipidaemia and a low-grade state of chronic inflammation. The aim of this pre-specified analysis of secondary outcome measures was to evaluate the effect of providing antenatal dietary and lifestyle advice on cardiometabolic and inflammatory biomarkers. METHODS: We conducted a multicentre trial in which pregnant women who were overweight or obese were randomised to receive either Lifestyle Advice or Standard Care. We report a range of pre-specified secondary maternal and newborn cardiometabolic and inflammatory biomarker outcomes. Maternal whole venous blood was collected at trial entry (mean 14 weeks gestation; non-fasting), at 28 weeks gestation (fasting), and at 36 weeks gestation (non-fasting). Cord blood was collected after birth and prior to the delivery of the placenta. A range of cardiometabolic and inflammatory markers were analysed (total cholesterol, triglycerides, non-esterified fatty acids, high-density lipoprotein cholesterol, insulin, glucose, leptin, adiponectin, C-reactive protein, granulocyte macrophage-colony stimulating factor, interferon gamma, TNF-α, and interleukins 1ß, 2, 4, 5, 6, 8, and 10). Participants were analysed in the groups to which they were randomised, and were included in the analyses if they had a measure at any time point. RESULTS: One or more biological specimens were available from 1951 women (989 Lifestyle Advice and 962 Standard Care), with cord blood from 1174 infants (596 Lifestyle Advice and 578 Standard Care). There were no statistically significant differences in mean cardiometabolic and inflammatory marker concentrations across pregnancy and in infant cord blood between treatment groups. Estimated treatment group differences were close to zero, with 95% confidence intervals spanning a range of differences that were short of clinical relevance. There was no evidence to suggest that the intervention effect was modified by maternal BMI category. CONCLUSIONS: Despite our findings, it will be worth considering potential relationships between cardiometabolic and inflammatory markers and clinical outcomes, including longer-term infant health and adiposity. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426 ; Date Registered 09/03/2007).

Sample size calculations for randomised trials including both independent and paired data.

Randomised trials including a mixture of independent and paired data arise in many areas of health research, yet methods for determining the sample size for such trials are lacking. We derive design effects algebraically assuming clustering because of paired data will be taken into account in the analysis using generalised estimating equations with either an independence or exchangeable working correlation structure. Continuous and binary outcomes are considered, along with three different methods of randomisation: cluster randomisation, individual randomisation and randomisation to opposite treatment groups. The design effect is shown to depend on the intracluster correlation coefficient, proportion of observations belonging to a pair, working correlation structure, type of outcome and method of randomisation. The derived design effects are validated through simulation and example calculations are presented to illustrate their use in sample size planning. These design effects will enable appropriate sample size calculations to be performed for future randomised trials including both independent and paired data. Copyright © 2017 John Wiley & Sons, Ltd.

Treatment of missing data in follow-up studies of randomised controlled trials: A systematic review of the literature.

BACKGROUND/AIMS: After completion of a randomised controlled trial, an extended follow-up period may be initiated to learn about longer term impacts of the intervention. Since extended follow-up studies often involve additional eligibility restrictions and consent processes for participation, and a longer duration of follow-up entails a greater risk of participant attrition, missing data can be a considerable threat in this setting. As a potential source of bias, it is critical that missing data are appropriately handled in the statistical analysis, yet little is known about the treatment of missing data in extended follow-up studies. The aims of this review were to summarise the extent of missing data in extended follow-up studies and the use of statistical approaches to address this potentially serious problem. METHODS: We performed a systematic literature search in PubMed to identify extended follow-up studies published from January to June 2015. Studies were eligible for inclusion if the original randomised controlled trial results were also published and if the main objective of extended follow-up was to compare the original randomised groups. We recorded information on the extent of missing data and the approach used to treat missing data in the statistical analysis of the primary outcome of the extended follow-up study. RESULTS: Of the 81 studies included in the review, 36 (44%) reported additional eligibility restrictions and 24 (30%) consent processes for entry into extended follow-up. Data were collected at a median of 7 years after randomisation. Excluding 28 studies with a time to event primary outcome, 51/53 studies (96%) reported missing data on the primary outcome. The median percentage of randomised participants with complete data on the primary outcome was just 66% in these studies. The most common statistical approach to address missing data was complete case analysis (51% of studies), while likelihood-based analyses were also well represented (25%). Sensitivity analyses around the missing data mechanism were rarely performed (25% of studies), and when they were, they often involved unrealistic assumptions about the mechanism. CONCLUSION: Despite missing data being a serious problem in extended follow-up studies, statistical approaches to addressing missing data were often inadequate. We recommend researchers clearly specify all sources of missing data in follow-up studies and use statistical methods that are valid under a plausible assumption about the missing data mechanism. Sensitivity analyses should also be undertaken to assess the robustness of findings to assumptions about the missing data mechanism.

Association of cord blood vitamin D with early childhood growth and neurodevelopment.

AIM: The association between fetal vitamin D [25-hydroxyvitamin D (25(OH)D)] exposure and early child growth and neurodevelopment is controversial. The aim of this study was to investigate the association between cord blood 25(OH)D and birth size, childhood growth and neurodevelopment. METHODS: Cord blood samples from 1040 Australian women enrolled in a randomised trial of docosahexaenoic acid (DHA) supplementation during pregnancy were analysed for 25(OH)D using mass spectroscopy. Infant length, weight and head circumference were measured at delivery. A sub-sample of 337 infants with cord blood samples were selected for growth and neurodevelopment assessment at 18 months and 4 years of age. Associations between standardised 25(OH)D and outcomes were assessed, taking into account DHA treatment, social and demographic variables. RESULTS: Standardised 25(OH)D in cord blood was not associated with length, weight or head circumference at birth, 18 months or 4 years of age. 25(OH)D was not associated with cognitive, motor, social-emotional or adaptive behaviour scores at 18 months, or cognitive score at 4 years of age. A 10 nmol/L increase in cord blood 25(OH)D was associated with a modest increase in average Language scores of 0.60 points at 18 months (adjusted 95% CI 0.04-1.17, P = .04) and 0.68 points at 4 years (adjusted 95% CI 0.07-1.29, P = .03) of age. CONCLUSIONS: Cord blood vitamin D was modestly, positively associated with language development in early childhood in our sample, although the magnitude of the association was small. Randomised controlled trials are needed to confirm a causal association and establish the potential clinical significance of the relationship between vitamin D status and language development.

The effect of antenatal dietary and lifestyle advice for women who are overweight or obese on emotional well-being: the LIMIT randomized trial.

INTRODUCTION: Our aim was to evaluate the effect of dietary and lifestyle advice given to women who were overweight or obese during pregnancy on maternal quality of life, anxiety and risk of depression, and satisfaction with care. MATERIAL AND METHODS: We conducted a randomized trial, involving pregnant women with body mass index ≥25 kg/m(2) , recruited from maternity units in South Australia. Women were randomized to Lifestyle Advice or Standard Care, and completed questionnaires assessing risk of depression (Edinburgh Postnatal Depression Scale), anxiety (Spielberger State-Trait Anxiety Inventory), and quality of life (SF-36) at trial entry, 28 and 36 weeks' gestation, and 4 months postpartum. Secondary trial outcomes assessed for this analysis were risk of depression, anxiety, maternal quality of life, and satisfaction with care. RESULTS: One or more questionnaires were completed by 976 of 1108 (90.8%) women receiving Lifestyle Advice and 957 of 1104 (89.7%) women receiving Standard Care. The risk of depression [adjusted risk ratio 1.01; 95% confidence interval (CI) 0.82-1.24; p = 0.95], anxiety (adjusted risk ratio 1.09; 95% CI 0.93-1.27; p = 0.31), and health-related quality of life were similar between the two groups. Women receiving Lifestyle Advice reported improved healthy food choice [Lifestyle Advice 404 (68.9%) vs. Standard Care 323 (51.8%); p < 0.0001], and exercise knowledge [Lifestyle Advice 444 (75.8%) vs. Standard Care 367 (58.8%); p < 0.0001], and reassurance about their health [Lifestyle Advice 499 (85.3%) vs. Standard Care 485 (77.9%); p = 0.0112], and health of their baby [Lifestyle Advice 527 (90.2%) vs. Standard Care 545 (87.6%); p = 0.0143]. CONCLUSION: Lifestyle advice in pregnancy improved knowledge and provided reassurance without negatively impacting well-being.

Analysis of Randomised Trials Including Multiple Births When Birth Size Is Informative.

BACKGROUND: Informative birth size occurs when the average outcome depends on the number of infants per birth. Although analysis methods have been proposed for handling informative birth size, their performance is not well understood. Our aim was to evaluate the performance of these methods and to provide recommendations for their application in randomised trials including infants from single and multiple births. METHODS: Three generalised estimating equation (GEE) approaches were considered for estimating the effect of treatment on a continuous or binary outcome: cluster weighted GEEs, which produce treatment effects with a mother-level interpretation when birth size is informative; standard GEEs with an independence working correlation structure, which produce treatment effects with an infant-level interpretation when birth size is informative; and standard GEEs with an exchangeable working correlation structure, which do not account for informative birth size. The methods were compared through simulation and analysis of an example dataset. RESULTS: Treatment effect estimates were affected by informative birth size in the simulation study when the effect of treatment in singletons differed from that in multiples (i.e. in the presence of a treatment group by multiple birth interaction). The strength of evidence supporting the effectiveness of treatment varied between methods in the example dataset. CONCLUSIONS: Informative birth size is always a possibility in randomised trials including infants from both single and multiple births, and analysis methods should be pre-specified with this in mind. We recommend estimating treatment effects using standard GEEs with an independence working correlation structure to give an infant-level interpretation.

Applying the intention-to-treat principle in practice: Guidance on handling randomisation errors.

BACKGROUND: The intention-to-treat principle states that all randomised participants should be analysed in their randomised group. The implications of this principle are widely discussed in relation to the analysis, but have received limited attention in the context of handling errors that occur during the randomisation process. The aims of this article are to (1) demonstrate the potential pitfalls of attempting to correct randomisation errors and (2) provide guidance on handling common randomisation errors when they are discovered that maintains the goals of the intention-to-treat principle. METHODS: The potential pitfalls of attempting to correct randomisation errors are demonstrated and guidance on handling common errors is provided, using examples from our own experiences. RESULTS: We illustrate the problems that can occur when attempts are made to correct randomisation errors and argue that documenting, rather than correcting these errors, is most consistent with the intention-to-treat principle. When a participant is randomised using incorrect baseline information, we recommend accepting the randomisation but recording the correct baseline data. If ineligible participants are inadvertently randomised, we advocate keeping them in the trial and collecting all relevant data but seeking clinical input to determine their appropriate course of management, unless they can be excluded in an objective and unbiased manner. When multiple randomisations are performed in error for the same participant, we suggest retaining the initial randomisation and either disregarding the second randomisation if only one set of data will be obtained for the participant, or retaining the second randomisation otherwise. When participants are issued the incorrect treatment at the time of randomisation, we propose documenting the treatment received and seeking clinical input regarding the ongoing treatment of the participant. CONCLUSION: Randomisation errors are almost inevitable and should be reported in trial publications. The intention-to-treat principle is useful for guiding responses to randomisation errors when they are discovered.

Association of cord blood vitamin D at delivery with postpartum depression in Australian women.

BACKGROUND: Observational studies have implicated low serum vitamin D (25-hydroxyvitamin D (25(OH)D)) levels in the development of mood disorders. Postpartum depression (PPD) is an important public health issue, although little is known about its association with serum 25(OH)D. AIMS: To determine the association between 25(OH)D at delivery and the subsequent risk of PPD at six weeks and six months postpartum in a large cohort of Australian women. MATERIALS AND METHODS: Cord blood samples from 1040 women participating in the docosahexaenoic acid (DHA) to Optimise Maternal Infant Outcome randomised controlled trial were analysed for 25(OH)D by mass spectroscopy. Maternal PPD was assessed using the Edinburgh Postnatal Depression Scale at six weeks and six months postpartum. The association between standardised 25(OH)D and PPD was assessed, taking into account DHA treatment, social and demographic variables. RESULTS: There was no association between cord blood 25(OH)D concentration at delivery and PPD at either six weeks or six months postpartum. Cord blood 25(OH)D 25-50 and >50 nmol/L at delivery was associated with decreased risk of PPD at six weeks postpartum compared with 25(OH)D <25 nmol/L in the control group, but not the DHA group. There was no association between cord blood 25(OH)D <25 nmol/L at delivery and PPD at six months postpartum. CONCLUSIONS: This largest study to date of 25(OH)D levels at delivery and PPD did not reveal a consistent link with PPD.

The effects of antenatal dietary and lifestyle advice for women who are overweight or obese on maternal diet and physical activity: the LIMIT randomised trial.

BACKGROUND: Overweight and obesity is a significant health concern during pregnancy. Our aim was to investigate the effect of providing antenatal dietary and lifestyle advice to women who are overweight or obese on components of maternal diet and physical activity. METHODS: We conducted a randomised controlled trial, in which pregnant women with a body mass index≥25 kg/m2, and singleton gestation between 10(+0) to 20(+0) weeks were recruited and randomised to Lifestyle Advice (involving a comprehensive dietary and lifestyle intervention over their pregnancy) or Standard Care. Within the intervention group, we conducted a nested randomised trial in which a subgroup of women were further randomised to receive access to supervised group walking sessions in addition to the standard information presented during the intervention contacts (the Walking group) or standard information only. The outcome measures were maternal dietary intake, (including food groups, macronutrient and micronutrient intake, diet quality (using the Healthy Eating Index; HEI), dietary glycaemic load, and glycaemic index) and maternal physical activity. Women completed the Harvard Semi-Structured Food Frequency Questionnaire, and the Short Questionnaire to Assess Health-enhancing Physical Activity (SQUASH), at trial entry, 28 and 36 weeks' gestational age, and 4 months postpartum. Analyses were performed on an intention-to-treat basis, using linear mixed effects models with adjustment for the stratification variables. RESULTS: Women randomised to Lifestyle Advice demonstrated a statistically significant increase in the number of servings of fruit and vegetables consumed per day, as well as increased consumption of fibre, and reduced percentage energy intake from saturated fats (P<0.05 for all). Maternal HEI was significantly improved at both 28 (73.35±6.62 versus 71.86±7.01; adjusted difference in means 1.58; 95% CI 0.89 to 2.27; P<0.0001) and 36 (72.95±6.82 versus 71.17±7.69; adjusted difference in means 1.77; 95% CI 1.01 to 2.53; P<0.0001) weeks. There were no differences in dietary glycaemic index or glycaemic load. Women randomised to Lifestyle Advice also demonstrated greater total physical activity (adjusted difference in means 359.76 metabolic equivalent task units (MET) minutes/week; 95% CI 74.87 to 644.65; P=0.01) compared with women receiving Standard Care. The supervised walking group was poorly utilised. CONCLUSIONS: For women who are overweight or obese, antenatal lifestyle advice improves maternal diet and physical activity during pregnancy. Please see related articles: http://www.biomedcentral.com/1741-7015/12/163 and http://www.biomedcentral.com/1741-7015/12/201. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ( ACTRN12607000161426).