Publications by authors named "Thomas R Sullivan"

52 Publications

Intracluster correlation coefficients in a large cluster randomized vaccine trial in schools: Transmission and impact of shared characteristics.

PLoS One 2021 14;16(10):e0254330. Epub 2021 Oct 14.

SAHMRI Women & Kids, South Australian Health & Medical Research Institute, Adelaide, Australia.

Cluster randomized trials (cRCT) to assess vaccine effectiveness incorporate indirect effects of vaccination, helping to inform vaccination policy. To calculate the sample size for a cRCT, an estimate of the intracluster correlation coefficient (ICC) is required. For infectious diseases, shared characteristics and social mixing behaviours may increase susceptibility and exposure, promote transmission and be a source of clustering. We present ICCs from a school-based cRCT assessing the effectiveness of a meningococcal B vaccine (Bexsero, GlaxoSmithKline) on reducing oropharyngeal carriage of Neisseria meningitidis (Nm) in 34,489 adolescents from 237 schools in South Australia in 2017/2018. We also explore the contribution of shared behaviours and characteristics to these ICCs. The ICC for carriage of disease-causing Nm genogroups (primary outcome) pre-vaccination was 0.004 (95% CI: 0.002, 0.007) and for all Nm was 0.007 (95%CI: 0.004, 0.011). Adjustment for social behaviours and personal characteristics reduced the ICC for carriage of disease-causing and all Nm genogroups by 25% (to 0.003) and 43% (to 0.004), respectively. ICCs are also reported for risk factors here, which may be outcomes in future research. Higher ICCs were observed for susceptibility and/or exposure variables related to Nm carriage (having a cold, spending ≥1 night out socializing or kissing ≥1 person in the previous week). In metropolitan areas, nights out socializing was a highly correlated behaviour. By contrast, smoking was a highly correlated behaviour in rural areas. A practical example to inform future cRCT sample size estimates is provided.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254330PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516260PMC
October 2021

'B Part of It' School Leaver study: a repeat cross-sectional study to assess the impact of increasing coverage with meningococcal B (4CMenB) vaccine on carriage of Neisseria meningitidis.

J Infect Dis 2021 Sep 6. Epub 2021 Sep 6.

Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia.

Background: Recombinant protein-based vaccines targeting serogroup B meningococci protect against invasive disease, but impacts on carriage are uncertain. This study assessed carriage prevalence of disease-associated meningococci from 2018-2020, as the proportion of vaccinated adolescents increased following introduction of a school-based 4CMenB immunisation program.

Methods: Eligible participants who completed high school (age 17-25) in South Australia in the previous year had an oropharyngeal swab taken and completed a risk factor questionnaire. Disease-associated meningococci (genogroups A, B, C, W, X, Y) were detected by meningococcal and genogroup-specific polymerase chain reaction.

Results: The final analysis included 4104 participants in 2018, 2690 in 2019, and 1338 in 2020. The proportion vaccinated with 4CMenB increased from 43% in 2018, to 78% in 2019, and 76% in 2020. Carriage prevalence of disease-associated meningococci in 2018 was 225/4104 (5.5%). There was little difference between the carriage prevalence in 2019 (134/2690, 5.0%, adjusted odds ratio [aOR] 0.82, 95% CI 0.64-1.05) and 2020 (68/1338, 5.1% aOR 0.82, 95% CI 0.57-1.17) compared to 2018.

Conclusions: Increased 4CMenB uptake in adolescents was not associated with a decline in carriage of disease-associated meningococci. 4CMenB immunisation programs should focus on direct (individual) protection for groups at greatest risk of disease.
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http://dx.doi.org/10.1093/infdis/jiab444DOI Listing
September 2021

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

Stat Med 2021 Aug 15. Epub 2021 Aug 15.

Department of Paediatrics, The University of Melbourne, Melbourne, Victoria, Australia.

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.
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http://dx.doi.org/10.1002/sim.9166DOI Listing
August 2021

Protocol for assessing if behavioural functioning of infants born <29 weeks' gestation is improved by omega-3 long-chain polyunsaturated fatty acids: follow-up of a randomised controlled trial.

BMJ Open 2021 05 5;11(5):e044740. Epub 2021 May 5.

Discipline of Paediatrics, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, South Australia, Australia.

Introduction: During the last trimester of pregnancy, the fetal brain undergoes a rapid growth spurt and accumulates essential nutrients including docosahexaenoic acid (DHA). This takes place ex-utero for infants born <29 weeks' gestation, without the in-utero provisions of DHA. Infants born <29 weeks' are more likely to experience behavioural and emotional difficulties than their term-born counterparts. It has been hypothesised that supplementing preterm infants with dietary DHA may alleviate insufficiency and subsequently prevent or minimise behavioural problems. This protocol describes a follow-up of infants born <29 weeks gestation who were enrolled in a randomised controlled trial (RCT) of DHA supplementation. We aim to determine whether DHA supplementation improves the behaviour, and general health of these infants.

Methods And Analysis: Infants born <29 weeks' gestation were enrolled in a multicentre blinded RCT of enteral DHA supplementation. Infants were randomised to receive an enteral emulsion that provided 60 mg/kg/day of DHA or a control emulsion commenced within the first 3 days of enteral feeding, until 36 weeks' postmenstrual age or discharge home, whichever occurred first. Families of surviving children (excluding those who withdrew from the study) from the Australian sites (up to 955) will be invited to complete a survey. The survey will include questions regarding child behavioural and emotional functioning, executive functioning, respiratory health and general health. We hypothesise that the DHA intervention will have a benefit on the primary outcome, parent-rated behaviour and emotional status as measured using the Total Difficulties score of the Strengths and Difficulties Questionnaire. Detecting a 2-point difference between groups (small effect size of 0.25 SD) with 90% power will require follow-up of 676 participants.

Ethics And Dissemination: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/16/WCHN/184). Results will be disseminated in peer-reviewed publications and conference presentations.

Trial Registration Number: ACTRN12612000503820.
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http://dx.doi.org/10.1136/bmjopen-2020-044740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103387PMC
May 2021

Maternal Late-Pregnancy Serum Unmetabolized Folic Acid Concentrations Are Not Associated with Infant Allergic Disease: A Prospective Cohort Study.

J Nutr 2021 Jun;151(6):1553-1560

School of Medicine, The University of Western Australia, Crawley, Australia.

Background: The increase in childhood allergic disease in recent decades has coincided with increased folic acid intakes during pregnancy. Circulating unmetabolized folic acid (UMFA) has been proposed as a biomarker of excessive folic acid intake.

Objective: We aimed to determine if late-pregnancy serum UMFA and total folate concentrations were associated with allergic disease risk in the offspring at 1 y of age in a population at high risk of allergy.

Methods: The cohort consisted of 561 mother-infant pairs from Western Australia. To be eligible the infant had to have a first-degree relative (mother, father, or sibling) with a history of medically diagnosed allergic disease. Maternal venous blood was collected between 36 and 40 wk of gestation. Serum UMFA was measured by LC-tandem MS. Serum total folate was determined using a microbiological method with chloramphenicol-resistant Lactobacillus rhamnosus as the test organism, and was collected between 36 and 40 wk of gestation. UMFA concentrations were measured by tandem MS using stable isotope dilution; folate concentrations were determined using the microbiological method with standardized kits. Infant allergic disease outcomes of medically diagnosed eczema, steroid-treated eczema, atopic eczema, IgE-mediated food allergy, allergen sensitization, and medically diagnosed wheeze were assessed at 1 y of age.

Results: Median (IQR) concentrations for UMFA and serum folate were 1.6 (0.6-4.7) and 53.2 (32.6-74.5) nmol/L, respectively. Of the infants, 34.6% had medically diagnosed eczema, 26.4% allergen sensitization, and 14.9% had an IgE-mediated food allergy. In both adjusted and unadjusted models there was little evidence of association between UMFA or serum folate and any of the infant allergy outcomes.

Conclusions: In this cohort of children at high risk of allergic disease there was no association between maternal UMFA or serum folate concentrations measured in late pregnancy and allergic disease outcomes at 1 y of age.
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http://dx.doi.org/10.1093/jn/nxab040DOI Listing
June 2021

Impact of Meningococcal B Vaccine on Invasive Meningococcal Disease in Adolescents.

Clin Infect Dis 2021 07;73(1):e233-e237

Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia.

Background: From 2017, a statewide cluster randomized trial was conducted in South Australia to assess the impact of the meningococcal B vaccine 4CMenB on pharyngeal Neisseria meningitidis carriage in adolescents. Senior schools were randomized to receive the vaccine in 2017 (intervention) or 2018 (control). In this study we report the vaccine impact of 4CMenB on serogroup B invasive meningococcal disease (IMD) in 16- to 19-year-old adolescents in South Australia.

Methods: This observational time series analysis of serogroup B IMD cases compares the 14 years prior to the commencement of the trial (2003-2016) with the 2 years following 4CMenB vaccination of the 2017 adolescent cohort.

Results: Approximately 62% of year 10 and 11 students (15-16 years old) in South Australia enrolled in the trial. A total of 30 522 year 10-12 students received at least 1 dose of 4CMenB. The number of serogroup B IMD cases in 16- to 19-year old adolescents in South Australia increased on average by 10% per year from 2003 to 2016 (95% confidence interval [CI], 6%-15%, P < .001), peaking with 10 cases in 2015. Serogroup B IMD cases reduced to 5 in 2017-2018 and 1 in 2018-2019, below the expected numbers of 9.9 (95% prediction interval [PI], 3.9-17.5) and 10.9 (95% PI, 4.4-19.1), respectively. This translated to an overall reduction in the number of serogroup B IMD cases of 71% (95% CI, 15%-90%, P = .02). There were no serogroup B IMD cases in vaccinated adolescents.

Conclusions: Vaccinating adolescents with 4CMenB was associated with a reduction in group B meningococcal disease in South Australia.

Clinical Trials Registration: NCT03089086.
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http://dx.doi.org/10.1093/cid/ciaa1636DOI Listing
July 2021

Protocol for assessing whether cognition of preterm infants <29 weeks' gestation can be improved by an intervention with the omega-3 long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA): a follow-up of a randomised controlled trial.

BMJ Open 2021 02 5;11(2):e041597. Epub 2021 Feb 5.

Women and Kids, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Introduction: Docosahexaenoic acid (DHA) is an omega-3 (n-3) fatty acid that accumulates into neural tissue during the last trimester of pregnancy, as the fetal brain is undergoing a growth spurt. Infants born <29 weeks' gestation are deprived the normal in utero supply of DHA during this period of rapid brain development. Insufficient dietary DHA postnatally may contribute to the cognitive impairments common among this population. This follow-up of the N-3 fatty acids for improvement in respiratory outcomes (N3RO) randomised controlled trial aims to determine if enteral DHA supplementation in infants born <29 weeks' gestation during the first months of life improves cognitive development at 5 years of age corrected for prematurity.

Methods And Analysis: N3RO was a randomised controlled trial of enteral DHA supplementation (60 mg/kg/day) or a control emulsion (without DHA) in 1273 infants born <29 weeks' gestation to determine the effect on bronchopulmonary dysplasia (BPD). We showed that DHA supplementation did not reduce the risk of BPD and may have increased the risk.In this follow-up at 5 years' corrected age, a predefined subset (n=655) of children from five Australian sites will be invited to attend a cognitive assessment with a psychologist. Children will be administered the Wechsler Preschool and Primary Scale of Intelligence (fourth edition) and a measure of inhibitory control (fruit stroop), while height, weight and head circumference will be measured.The primary outcome is full-scale IQ. To ensure 90% power, a minimum of 592 children are needed to detect a four-point difference in IQ between the groups.Research personnel and families remain blinded to group assignment.

Ethics And Dissemination: The Women's and Children Health Network Human Research Ethics Committee reviewed and approved the study (HREC/17/WCHN/187). Caregivers will give informed consent prior to taking part in this follow-up study. Findings of this study will be disseminated through peer-reviewed publications and conference presentations.

Trial Registration Number: ACTRN12612000503820.
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http://dx.doi.org/10.1136/bmjopen-2020-041597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925903PMC
February 2021

Effectiveness of Meningococcal Vaccines at Reducing Invasive Meningococcal Disease and Pharyngeal Neisseria meningitidis Carriage: A Systematic Review and Meta-analysis.

Clin Infect Dis 2021 08;73(3):e609-e619

Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network, Adelaide, South Australia, Australia.

Background: Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, leads to significant morbidity and mortality worldwide. This review aimed to establish the effectiveness of meningococcal vaccines at preventing IMD and N. meningitidis pharyngeal carriage.

Methods: A search within PubMed, Embase, Scopus, and unpublished studies up to 1 February 2020 was conducted.

Results: After removal of duplicates, 8565 studies were screened and 27 studies included. Protection was provided by meningococcal C vaccines for group C IMD (odds ratio [OR], 0.13 [95% confidence interval {CI}, .07-.23]), outer membrane vesicle (OMV) vaccines against group B IMD (OR, 0.35 [95% CI, .25-.48]), and meningococcal A, C, W, Y (MenACWY) vaccines against group ACWY IMD (OR, 0.31 [95% CI, .20-.49]). A single time series analysis found a reduction following an infant 4CMenB program (incidence rate ratio, 0.25 [95% CI, .19-.36]). Multivalent MenACWY vaccines did not reduce carriage (relative risk [RR], 0.88 [95% CI, .66-1.18]), unlike monovalent C vaccines (RR, 0.50 [95% CI, .26-.97]). 4CMenB vaccine had no effect on group B carriage (RR, 1.12 [95% CI, .90-1.40]). There was also no reduction in group B carriage following MenB-FHbp vaccination (RR, 0.98 [95% CI, .53-1.79]).

Conclusions: Meningococcal conjugate C, ACWY, and OMV vaccines are effective at reducing IMD. A small number of studies demonstrate that monovalent C conjugate vaccines reduce pharyngeal N. meningitidis carriage. There is no evidence of carriage reduction for multivalent MenACWY, OMV, or recombinant MenB vaccines, which has implications for immunization strategies.

Clinical Trials Registration: CRD42018082085 (PROSPERO).
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http://dx.doi.org/10.1093/cid/ciaa1733DOI Listing
August 2021

The efficacy and safety of peripheral intravenous parenteral nutrition vs 10% glucose in preterm infants born 30 to 33 weeks' gestation: a randomised controlled trial.

BMC Pediatr 2020 08 17;20(1):384. Epub 2020 Aug 17.

SAHMRI Women and Kids, South Australian Health and Medical Research Institute Adelaide, South Australia, Australia.

Background: Preterm infants born 30 to 33 weeks' gestation often require early support with intravenous fluids because of respiratory distress, hypoglycemia or feed intolerance. When full feeds are anticipated to be reached within the first week, risks associated with intravenous delivery mode and type must be carefully considered. Recommendations are for parenteral nutrition to be infused via central venous lines (because of the high osmolarity), however, given the risks associated with central lines, clinicians may opt for 10% glucose via peripheral venous catheter when the need is short-term. We therefore compare a low osmolarity peripheral intravenous parenteral nutrition (P-PN) solution with peripheral intravenous 10% glucose on growth rate in preterm infants born 30 to 33 weeks' gestation.

Methods: In this parallel group, single centre, superiority, non-blinded, randomised controlled trial, 92 (P-PN 42, control 50) infants born 30 to 33 weeks' gestation, were randomised within 24 h of age, to receive either P-PN (8% glucose, 30 g/L amino acids, 500 IU/L heparin and SMOFlipid®) or a control of peripheral intravenous 10% glucose. Both groups received enteral feeds according to hospital protocol. The primary outcome was rate of weight gain from birth to 21 days of age.

Results: The rate of weight gain was significantly increased in P-PN infants compared with control (P-PN, n = 42, 18.7, SD 6.6 g/d vs control, n = 50, 14.8, SD 6.0 g/d; adjusted mean difference 3.9 g/d, 95% CI 1.3 to 6.6; P = 0.004), with the effect maintained to discharge home. Days to regain birthweight were significantly reduced and length gain significantly increased in P-PN infants. One infant in the P-PN group had a stage 3 extravasation which rapidly resolved. Blood urea nitrogen and triglyceride levels were significantly higher in the P-PN group in the first week of life, but there were no instances of abnormally high levels. There were no significant differences in any other clinical or biochemical outcomes.

Conclusion: P-PN improves the rate of weight gain to discharge home in preterm infants born 30 to 33 weeks gestation compared with peripheral intravenous 10% glucose.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12616000925448 . Registered 12 July 2016.
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http://dx.doi.org/10.1186/s12887-020-02280-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429781PMC
August 2020

Micronutrient intake and prevalence of micronutrient inadequacy among women (15-49 y) and children (6-59 mo) in South Kivu and Kongo Central, Democratic Republic of the Congo (DRC).

PLoS One 2020 12;15(6):e0223393. Epub 2020 Jun 12.

Division of Healthy Mothers, Babies & Children, South Australian Health and Medical Research Institute, Adelaide, SA, Australia.

Iron biofortified beans and carotenoid enriched cassava are proposed as a solution to combat iron and vitamin A deficiencies, respectively, in the Democratic Republic of Congo (DRC). To inform the need for biofortified foods, we conducted a survey in 2014 in two provinces of the DRC, South Kivu and Kongo Central. Unexpectedly, women of reproductive age (WRA; 15-49 y) and their children (6-59 m) had a low prevalence of biochemical iron and vitamin A deficiency, based on ferritin and retinol binding protein, respectively. To better understand the lack of biochemical deficiency of these nutrients, we examined the prevalence of inadequate intake for these and other select nutrients. Dietary intake was assessed using 24-hour recalls among 744 mother-child dyads. Repeat recalls on a non-consecutive day were conducted with a subsample of the study population to account for intra-individual variation and estimate usual intake. In WRA, the prevalence of inadequate iron intakes were 33% and 29% in South Kivu and Kongo Central, respecitvely. The prevalence of inadequate vitamin A intakes among WRA was low in South Kivu (18%) and negligible in Kongo Central (1%). Iron inadequacy was highest in infants (6-11 m) at 82% and 64% in South Kivu and Kongo Central, respectively. Among older children (12-59 m) in both provinces, the prevalence of iron inadequacy was similar at ~20%. There was a high prevalence of inadequate zinc intake in women and children (i.e. 79-86% among WRA and 56-91% among children 6-59 m) consistent with our findings of a high prevalence of low serum zinc in the same sample. Dietary data here corroborate the low prevalence of biochemical vitamin A deficiency but not iron. However, any change to the supply of red palm oil (primary source of vitamin A) would dramatically reduce population vitamin A intakes, thus a carotenoid enriched cassava program may be beneficial as a safety net measure. Crops biofortified with zinc also appear warranted. We caution that our findings cannot be extrapolated to the entire Congo where diverse agro-ecological landscape exist or when political and environmental shocks occur which challenge food production.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223393PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292409PMC
August 2020

Linking data from a large clinical trial with the Australian Cerebral Palsy Register.

Dev Med Child Neurol 2020 10 8;62(10):1170-1175. Epub 2020 May 8.

Discipline of Obstetrics and Gynaecology, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.

Aim: To link data from a large maternal perinatal trial with the Australian Cerebral Palsy Register (ACPR) to identify children with cerebral palsy (CP).

Method: Deidentified data from the Australasian Collaborative Trial of Magnesium Sulphate (ACTOMgSO ) and the ACPR were linked. Children born from 1996 to 2000 at Australian hospitals who survived and had 2-year paediatric assessments were included. Children identified with CP in: (1) both the ACTOMgSO (2y) and the ACPR (5y), (2) the ACTOMgSO only, and (3) the ACPR only were compared.

Results: We included 913 children (492 males, 421 females; mean gestational age at birth 27.8wks [standard deviation 2.1wks]; range 23.0-40.0wks). Eighty-four children received a CP diagnosis: 35 by the ACTOMgSO and the ACPR, 29 by the ACTOMgSO only, and 20 by the ACPR only. The ACTOMgSO diagnosed 76.2% (95% confidence interval [CI] 65.9-84.1) and the ACPR identified 65.5% (95% CI 54.7-74.9). Children born in states/territories with long-standing versus more recently established registers were more likely to be included on the ACPR (p<0.05).

Interpretation: Linking deidentified perinatal trial data with the ACPR was achieved. Limitations of both strategies for identifying children with CP in this era (late 1990s and early 2000s) probably explain many of the differences observed, and inform future linkage studies and evaluations of CP-preventive interventions.

What This Paper Adds: Randomized trial data were linked with the Australian Cerebral Palsy Register. Trial (2y) and register (up to 5y) diagnoses of cerebral palsy (CP) differed. States with long-standing registers were more likely to include children with CP.
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http://dx.doi.org/10.1111/dmcn.14556DOI Listing
October 2020

Red Blood Cell Folate Likely Overestimated in Australian National Survey: Implications for Neural Tube Defect Risk.

Nutrients 2020 May 1;12(5). Epub 2020 May 1.

Women and Kids Theme, South Australian Health and Medical Research Institute, Adelaide 5000, South Australia, Australia.

In 2009, the Australian government mandated the addition of folic acid to bread flour to reduce the incidence of neural tube defects (NTD)-affected pregnancies. In 2011-2012, the Australian Health Measures Survey (AHMS) reported a mean red blood cell (RBC) folate in women of reproductive age (16-44 y) of 1647 nmol/L. Over 99% of women had an RBC folate ≥ 906 nmol/L, a concentration consistent with a very low risk of NTDs if a woman became pregnant. However, RBC folate was measured using an immunoassay, which is not a recommended method due to questionable accuracy. The microbiological assay is the preferred method for RBC folate measurement. To determine whether the immunoassay method may have led to spurious conclusions about the folate status of Australian women, we collected fasting blood samples from 74 healthy non-pregnant, non-lactating women (18-44 y) and measured RBC folate using both the immunoassay and microbiological methods. Mean RBC folate (95% confidence interval) concentration measured with the immunoassay method was 1735 (1666, 1804) nmol/L compared with 942 (887, 1012) nmol/L using the microbiological method. No woman had an RBC folate < 906 nmol/L using the immunoassay method, whereas 46% of women had an RBC folate < 906 nmol/L using the microbiological method. The NTD risk was estimated to be 0.06% using the immunoassay method and 0.14% using the microbiological method. RBC folate using AHMS survey may have underestimated NTD risk in Australian women.
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http://dx.doi.org/10.3390/nu12051283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281964PMC
May 2020

Adjusting for Treatment Switching in Oncology Trials: A Systematic Review and Recommendations for Reporting.

Value Health 2020 03 23;23(3):388-396. Epub 2020 Jan 23.

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Objectives: To systematically review the quality of reporting on the application of switching adjustment approaches in published oncology trials and industry submissions to the National Institute for Health and Care Excellence Although methods such as the rank preserving structural failure time model (RPSFTM) and inverse probability of censoring weights (IPCW) have been developed to address treatment switching, the approaches are not widely accepted within health technology assessment. This limited acceptance may partly be a consequence of poor reporting on their application.

Methods: Published trials and industry submissions were obtained from searches of PubMed and nice.org.uk, respectively. The quality of reporting in these studies was judged against a checklist of reporting recommendations, which was developed by the authors based on detailed considerations of the methods.

Results: Thirteen published trials and 8 submissions to nice.org.uk satisfied inclusion criteria. The quality of reporting around the implementation of the RPSFTM and IPCW methods was generally poor. Few studies stated whether the adjustment approach was prespecified, more than a third failed to provide any justification for the chosen method, and nearly half neglected to perform sensitivity analyses. Further, it was often unclear how the RPSFTM and IPCW methods were implemented.

Conclusions: Inadequate reporting on the application of switching adjustment methods increases uncertainty around results, which may contribute to the limited acceptance of these methods by decision makers. The proposed reporting recommendations aim to support the improved interpretation of analyses undertaken to adjust for treatment switching.
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http://dx.doi.org/10.1016/j.jval.2019.10.015DOI Listing
March 2020

Meningococcal B Vaccine and Meningococcal Carriage in Adolescents in Australia.

N Engl J Med 2020 01;382(4):318-327

From the Vaccinology and Immunology Research Trials Unit, Women's and Children's Health Network (H.S.M.), the Robinson Research Institute and Adelaide Medical School (H.S.M., M.M.), and the School of Public Health (T.R.S.), University of Adelaide, the Communicable Disease Control Branch, SA Health (A.P.K.), and SA Pathology (A.L.), Adelaide, and the Marshall Centre for Infectious Disease Research and Training, School of Biomedical Science (C.M.K.), and the School of Medicine (P.R.), University of Western Australia, the Departments of General Paediatrics and Immunology, Perth Children's Hospital (P.R.), and Wesfarmers Centre of Vaccines and Infectious Diseases, Telethon Kid's Institute (P.R.), Perth - all in Australia; the Department of Zoology, University of Oxford, Oxford (J.M.M., M.C.J.M.), the Immunization Department, Public Health England, London (S.N.L., M.E.R., C.T.), the Departments of Pathology and Veterinary Medicine, University of Cambridge, Cambridge (C.T.), the Meningococcal Reference Unit, Public Health England, Manchester (R.B.), and Bristol Children's Vaccine Centre, Schools of Cellular and Molecular Medicine and of Population Health Sciences, University of Bristol, Bristol (A.F.) - all in the United Kingdom; GlaxoSmithKline Vaccines, Amsterdam (J.W.); and GlaxoSmithKline Vaccines, Rockville, MD (K.V.).

Background: The meningococcal group B vaccine 4CMenB is a new, recombinant protein-based vaccine that is licensed to protect against invasive group B meningococcal disease. However, its role in preventing transmission and, therefore, inducing population (herd) protection is uncertain.

Methods: We used cluster randomization to assign, according to school, students in years 10 to 12 (age, 15 to 18 years) in South Australia to receive 4CMenB vaccination either at baseline (intervention) or at 12 months (control). The primary outcome was oropharyngeal carriage of disease-causing (group A, B, C, W, X, or Y) in students in years 10 and 11, as identified by polymerase-chain-reaction assays for (encoding porin protein A) and genogroups. Secondary outcomes included carriage prevalence and acquisition of all and individual disease-causing genogroups. Risk factors for carriage were assessed at baseline.

Results: A total of 237 schools participated. During April through June 2017, a total of 24,269 students in years 10 and 11 and 10,220 students in year 12 were enrolled. At 12 months, there was no difference in the prevalence of carriage of disease-causing between the vaccination group (2.55%; 326 of 12,746) and the control group (2.52%; 291 of 11,523) (adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.80 to 1.31; P = 0.85). There were no significant differences in the secondary carriage outcomes. At baseline, the risk factors for carriage of disease-causing included later year of schooling (adjusted odds ratio for year 12 vs. year 10, 2.75; 95% CI, 2.03 to 3.73), current upper respiratory tract infection (adjusted odds ratio, 1.35; 95% CI, 1.12 to 1.63), cigarette smoking (adjusted odds ratio, 1.91; 95% CI, 1.29 to 2.83), water-pipe smoking (adjusted odds ratio, 1.82; 95% CI, 1.30 to 2.54), attending pubs or clubs (adjusted odds ratio, 1.54; 95% CI, 1.28 to 1.86), and intimate kissing (adjusted odds ratio, 1.65; 95% CI, 1.33 to 2.05). No vaccine safety concerns were identified.

Conclusions: Among Australian adolescents, the 4CMenB vaccine had no discernible effect on the carriage of disease-causing meningococci, including group B. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT03089086.).
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http://dx.doi.org/10.1056/NEJMoa1900236DOI Listing
January 2020

Docosahexaenoic acid supplementation of preterm infants and parent-reported symptoms of allergic disease at 7 years corrected age: follow-up of a randomized controlled trial.

Am J Clin Nutr 2019 06;109(6):1600-1610

Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

Background: Docosahexaenoic acid (DHA, 22:6n-3) supplementation in the prenatal period is associated with a reduction in the incidence of some symptoms of allergic disease. Infants born preterm are at increased risk of allergic disease, but it is unknown if DHA supplementation reduces the risk of childhood allergies.

Objectives: The aim of this study was to determine if supplementation of infants born at <33 wk gestation with high-DHA compared with standard-DHA enteral feeds decreases the incidence and severity of parent-reported allergic disease symptoms at a corrected age (CA) of 7 y.

Methods: This study was a follow-up of an Australian multicenter randomized controlled trial. Infants were given high-DHA (∼1% total fatty acids) or standard-DHA (∼0.3% total fatty acids) enteral feeds from 2-4 d of postnatal age until 40 wk postmenstrual age. Parent-reported incidence of respiratory allergic disease symptoms including wheeze and rhinitis at 7 y CA were the main outcomes. Other outcomes included the incidence of eczema symptoms; severity of any symptoms; and the incidence of wheeze, rhinitis, rhinoconjunctivitis, and eczema from birth to 7 y CA.

Results: Data were available for 569 of 657 (87%) children originally randomized. Symptoms of wheeze or rhinitis at 7 y CA did not differ between high- and standard-DHA groups [wheeze: RR: 1.10; 95% CI: 0.73, 1.65; P = 0.66; rhinitis: RR: 1.09; 95% CI: 0.81, 1.46; P = 0.59]. There was no difference in other allergic disease symptoms at 7 y CA or in the severity of symptoms. Parent-reported symptoms of wheeze, rhinitis, rhinoconjunctivitis, or eczema from birth to 7 y CA did not differ between the groups.

Conclusions: High-dose DHA supplementation of infants born at <33 wk gestation did not alter allergic disease symptoms or severity at 7 y CA, or from birth to 7 y CA compared with standard-dose DHA. This trial was registered with the Australian New Zealand Clinical Trials Registry as ANZCTR 12606000327583 (http://www.anzctr.org.au).
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http://dx.doi.org/10.1093/ajcn/nqz010DOI Listing
June 2019

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

Paediatr Perinat Epidemiol 2018 07 4;32(4):380-387. Epub 2018 May 4.

Melbourne Children's Trials Centre, Murdoch Children's Research Institute, Melbourne, VIC, Australia.

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.
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http://dx.doi.org/10.1111/ppe.12471DOI Listing
July 2018

Multiple imputation for handling missing outcome data when estimating the relative risk.

BMC Med Res Methodol 2017 Sep 6;17(1):134. Epub 2017 Sep 6.

The University of Adelaide, School of Public Health, Adelaide, SA, Australia.

Background: Multiple imputation is a popular approach to handling missing data in medical research, yet little is known about its applicability for estimating the relative risk. Standard methods for imputing incomplete binary outcomes involve logistic regression or an assumption of multivariate normality, whereas relative risks are typically estimated using log binomial models. It is unclear whether misspecification of the imputation model in this setting could lead to biased parameter estimates.

Methods: Using simulated data, we evaluated the performance of multiple imputation for handling missing data prior to estimating adjusted relative risks from a correctly specified multivariable log binomial model. We considered an arbitrary pattern of missing data in both outcome and exposure variables, with missing data induced under missing at random mechanisms. Focusing on standard model-based methods of multiple imputation, missing data were imputed using multivariate normal imputation or fully conditional specification with a logistic imputation model for the outcome.

Results: Multivariate normal imputation performed poorly in the simulation study, consistently producing estimates of the relative risk that were biased towards the null. Despite outperforming multivariate normal imputation, fully conditional specification also produced somewhat biased estimates, with greater bias observed for higher outcome prevalences and larger relative risks. Deleting imputed outcomes from analysis datasets did not improve the performance of fully conditional specification.

Conclusions: Both multivariate normal imputation and fully conditional specification produced biased estimates of the relative risk, presumably since both use a misspecified imputation model. Based on simulation results, we recommend researchers use fully conditional specification rather than multivariate normal imputation and retain imputed outcomes in the analysis when estimating relative risks. However fully conditional specification is not without its shortcomings, and so further research is needed to identify optimal approaches for relative risk estimation within the multiple imputation framework.
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http://dx.doi.org/10.1186/s12874-017-0414-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588607PMC
September 2017

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

Clin Trials 2017 Aug 6;14(4):387-395. Epub 2017 Apr 6.

1 School of Public Health, The University of Adelaide, Adelaide, SA, Australia.

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.
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http://dx.doi.org/10.1177/1740774517703319DOI Listing
August 2017

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

N Engl J Med 2017 03;376(13):1245-1255

From Healthy Mothers, Babies, and Children, South Australian Health and Medical Research Institute (C.T.C., M.M., A.J.M., R.A.G.), the Schools of Medicine (C.T.C., M.M., A.J.M., M.J.S.), Public Health (T.R.S.), and Agriculture, Food, and Wine (R.A.G.) and the Robinson Research Institute (M.J.S.), University of Adelaide, the Department of Neonatal Medicine, Women's and Children's Hospital (A.J.M., M.J.S.), and the School of Medicine (S.A.M.), Flinders University, Adelaide, SA, the Newborn Research Centre, Royal Women's Hospital (P.G.D., M.T.), University of Melbourne (P.G.D., M.T.), Murdoch Children's Research Institute (M.T.), the Department of Paediatrics, Mercy Hospital for Women (G.F.O., J.H.), the Department of Paediatrics, Monash University and Monash Newborn, Monash Children's Hospital (K.T.), Melbourne, VIC, the Clinical Trials Centre, University of Sydney (K.S.), School of Women's and Children's Health, University of New South Wales (K.L., J.S.), and Newborn Care, Royal Hospital for Women (S.B.), Sydney, the Neonatal Intensive Care Unit, John Hunter Children's Hospital and School of Medicine and Public Health, University of Newcastle, Newcastle, NSW (J.T.), the Neonatal Intensive Care Unit, Liverpool Hospital, Liverpool, NSW (J.S., I.R.C.), the Department of Newborn Medicine, Centre for Neonatal Research and Education, University of Western Australia, Perth (K.S.), and Newborn Services, Mater Misericordiae, and Mater Research Institute, University of Queensland, Brisbane (H.G.L.) - all in Australia; the Department of Paediatrics and Child Health, University of Otago, Wellington (M.J.B.), the Newborn Intensive Care Unit, Waikato Hospital, Hamilton (D.L.H.), and Liggins Institute, University of Auckland, Auckland (D.L.H.) - all in New Zealand; and the Department of Neonatology, KK Women's and Children's Hospital (V.S.R., M.-C.C., P.A.J.), Yong Loo Lin School of Medicine, National University of Singapore (V.S.R., M.-C.C.), and Duke-National University of Singapore Medical School (V.S.R., M.-C.C.) - all in Singapore.

Background: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking.

Methods: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first.

Results: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06).

Conclusions: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).
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http://dx.doi.org/10.1056/NEJMoa1611942DOI Listing
March 2017

Association Between Family Characteristics and the Effect of Timing of Regular Egg Introduction in Infant Egg Allergy.

JAMA Pediatr 2017 05;171(5):489-490

Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1001/jamapediatrics.2016.4978DOI Listing
May 2017

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

Stat Med 2017 04 10;36(8):1227-1239. Epub 2017 Jan 10.

Murdoch Children's Research Institute, Parkville, VIC, Australia.

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.
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http://dx.doi.org/10.1002/sim.7201DOI Listing
April 2017

Should multiple imputation be the method of choice for handling missing data in randomized trials?

Stat Methods Med Res 2018 09 19;27(9):2610-2626. Epub 2016 Dec 19.

3 Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Australia.

The use of multiple imputation has increased markedly in recent years, and journal reviewers may expect to see multiple imputation used to handle missing data. However in randomized trials, where treatment group is always observed and independent of baseline covariates, other approaches may be preferable. Using data simulation we evaluated multiple imputation, performed both overall and separately by randomized group, across a range of commonly encountered scenarios. We considered both missing outcome and missing baseline data, with missing outcome data induced under missing at random mechanisms. Provided the analysis model was correctly specified, multiple imputation produced unbiased treatment effect estimates, but alternative unbiased approaches were often more efficient. When the analysis model overlooked an interaction effect involving randomized group, multiple imputation produced biased estimates of the average treatment effect when applied to missing outcome data, unless imputation was performed separately by randomized group. Based on these results, we conclude that multiple imputation should not be seen as the only acceptable way to handle missing data in randomized trials. In settings where multiple imputation is adopted, we recommend that imputation is carried out separately by randomized group.
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http://dx.doi.org/10.1177/0962280216683570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393436PMC
September 2018

Development of Time- and Voltage-Domain Mapping (V-T-Mapping) to Localize Ventricular Tachycardia Channels During Sinus Rhythm.

Circ Arrhythm Electrophysiol 2016 12;9(12)

From the Centre for Heart Rhythm Disorders, South Australian Health and Medical Research Institute, University of Adelaide and Royal Adelaide Hospital, Australia (S.N., P.K., A.N.G., L.W., G.D.Y., P.S., K.C.R.-T.); and School of Public Health, University of Adelaide, Australia (T.R.S.).

Background: In ventricular scar, impulse spread is slow because it traverses split and zigzag channels of surviving muscle. We aimed to evaluate scar electrograms to determine their local delay (activation time) and inequality in voltage splitting (entropy), and their relationship to channels. We reasoned that unlike innocuous channels, which are often short with multiple side branches, ventricular tachycardia (VT) supporting channels have very slow impulse spread and possess low entropy because of their longer protected length and relative lack of side-branching.

Methods And Results: Patients with ischemic cardiomyopathy and multiple VT were studied. In initial mapping stage (16 patients and 58 VTs), left ventricular endocardial mapping was performed in sinus rhythm. Detailed pace mapping was used to identify VT channels and confirmed, when feasible, by entrainment. Scar electrograms were analyzed in time and voltage domains to determine mean activation time, dispersion in activation time, and entropy. Predictive performances of these properties to detect VT channels were tested. In the application stage (7 patients and 20 VTs), these properties were prospectively tested to guide catheter ablation. A mean number of 763±203 sampling points were taken. From 1770 pace maps, 47 channels corresponded to VTs. A combination of scar electrograms with the latest mean activation time and minimum entropy, in a high activation dispersion region, accurately recognized regions containing VT channels (κ=0.89, sensitivity=86%, specificity=100%, positive predictive value=93%, and negative predictive value=100%). Finally, focused ablation within 5-mm rim of the prospective channel regions eliminated 18 of 20 inducible VTs.

Conclusions: Activation time and entropy mapping in the scar accurately identify VT channels during sinus rhythm. The method integrates principles of reentry formation to recognize VT channels without pace mapping or mapping during VT.
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http://dx.doi.org/10.1161/CIRCEP.116.004050DOI Listing
December 2016

Randomized controlled trial of early regular egg intake to prevent egg allergy.

J Allergy Clin Immunol 2017 May 20;139(5):1600-1607.e2. Epub 2016 Aug 20.

Women's & Children's Health Research Institute, Adelaide, Australia; School of Medicine, University of Adelaide, Women's and Children's Health Network, Adelaide, Australia; Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, Australia.

Background: The ideal age to introduce egg into the infant diet has been debated for the past 2 decades in the context of rising rates of egg allergy.

Objective: We sought to determine whether regular consumption of egg protein from age 4 to 6 months reduces the risk of IgE-mediated egg allergy in infants with hereditary risk, but without eczema.

Methods: Infants aged 4 to 6 months were randomly allocated to receive daily pasteurized raw whole egg powder (n = 407) or a color-matched rice powder (n = 413) to age 10 months. All infants followed an egg-free diet and cooked egg was introduced to both groups at age 10 months. The primary outcome was IgE-mediated egg allergy defined by a positive pasteurized raw egg challenge and egg sensitization at age 12 months.

Results: There was no difference between groups in the percentage of infants with IgE-mediated egg allergy (egg 7.0% vs control 10.3%; adjusted relative risk, 0.75; 95% CI, 0.48-1.17; P = .20). A higher proportion of participants in the egg group stopped taking the study powder because of a confirmed allergic reaction (25 of 407 [6.1%] compared with 6 of 413 [1.5%]). Egg-specific IgG levels were substantially higher in the egg group at 12 months (median, 1.22 mg/L vs control 0.07 mg/L; P < .0001).

Conclusions: We found no evidence that regular egg intake from age 4 to 6 months substantially alters the risk of egg allergy by age 1 year in infants who are at hereditary risk of allergic disease and had no eczema symptoms at study entry.
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http://dx.doi.org/10.1016/j.jaci.2016.06.052DOI Listing
May 2017

Human milk intake in preterm infants and neurodevelopment at 18 months corrected age.

Pediatr Res 2016 10 24;80(4):486-92. Epub 2016 May 24.

Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts.

Background: The effect of human milk intake on neurodevelopment in preterm infants is uncertain.

Methods: We analyzed data from 611 participants in the DHA for Improvement of Neurodevelopmental Outcomes study, enrolled at ≤33 wk gestation from five Australian perinatal centers. The main exposures were (i) average daily human milk intake during the neonatal hospitalization and (ii) total duration of human milk intake before and after discharge. Outcomes were Bayley Scales of Infant Development, 2nd Edition Mental (MDI), and Psychomotor (PDI) Development Indexes.

Results: Adjusting for confounders in linear regression, human milk intake was not associated with higher MDI (0.2 points per 25 ml/kg/d; 95% confidence interval (CI): -0.6, 1.0) or PDI (-0.3 points; 95% CI: -1.1, 0.4). Longer duration of human milk intake was also not associated with MDI (0.1 points per month; 95% CI: -0.2, 0.3) or PDI (-0.2 points per month; 95% CI: -0.5, 0.01) scores, except in infants born 29-33 wk gestation (n = 364, MDI 0.3 points higher per additional month, 95% CI: 0.1, 0.6).

Conclusions: We found no associations of human milk intake during the neonatal hospitalization with neurodevelopment at 18 mo corrected age.
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http://dx.doi.org/10.1038/pr.2016.114DOI Listing
October 2016

The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks' gestation.

BMC Pediatr 2016 06 1;16:72. Epub 2016 Jun 1.

Department Neonatology, KK Women's and Children's Hospital, Singapore, Singapore.

Background: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and long-term respiratory and neurological morbidity in very preterm infants. While survival rates of very preterm infants have increased over the past two decades there has been no decrease in the rate of BPD in surviving infants. Evidence from animal and human studies has suggested potential benefits of docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid, in the prevention of chronic lung disease. This randomised controlled trial aims to determine the effectiveness of supplementary DHA in reducing the rate of BPD in infants less than 29 weeks' gestation.

Methods/design: This is a multicentre, parallel group, randomised, blinded and controlled trial. Infants born less than 29 weeks' gestation, within 3 days of first enteral feed and with parent informed consent are eligible to participate. Infants will be randomised to receive an enteral emulsion containing DHA or a control emulsion without DHA. The DHA emulsion will provide 60 mg/kg/day of DHA. The study emulsions will continue to 36 weeks' postmenstrual age (PMA). The primary outcome is BPD as assessed by the requirement for supplemental oxygen and/or assisted ventilation at 36 weeks' PMA. Secondary outcomes include the composite of death or BPD; duration of respiratory support and hospitalisation, major neonatal morbidities. The target sample size is 1244 infants (622 per group), which will provide 90 % power to detect a clinically meaningful absolute reduction of 10 % in the incidence of BPD between the DHA and control emulsion (two tailed α =0.05).

Discussion: DHA supplementation has the potential to reduce respiratory morbidity in very preterm infants. This multicentre trial will provide evidence on whether an enteral DHA supplement reduces BPD in very preterm infants.

Trial Registration: Australia and New Zealand Clinical Trial Registry: ACTRN12612000503820 . Registered 09 May 2012.
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http://dx.doi.org/10.1186/s12887-016-0611-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896378PMC
June 2016

Response to Klebanoff.

Paediatr Perinat Epidemiol 2016 Mar;30(2):206

MRC Biostatistics Unit, Cambridge, UK.

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http://dx.doi.org/10.1111/ppe.12271DOI Listing
March 2016

Higher cord blood 25-hydroxyvitamin D concentrations reduce the risk of early childhood eczema: in children with a family history of allergic disease.

World Allergy Organ J 2015 6;8(1):28. Epub 2015 Oct 6.

Women's & Children's Health Research Institute, University of Adelaide, North Adelaide, SA 5006 Australia ; Healthy Mothers, Babies and Children, South Australian Health and Medical Research Institute, Adelaide, SA 5000 Australia ; School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005 Australia.

Background: In recent years the role of vitamin D status in early life on the development of allergic disease has generated much interest. The aim of this study was to determine whether cord blood vitamin D concentrations were associated with risk of early childhood allergic disease.

Methods: Measurements of cord blood 25-hydroxyvitamin D [25(OH)D] concentrations were available in 270 mother-child pairs who were participating in the allergy follow-up (n = 706) of the Docosahexaenoic Acid to Optimise Mother Infant Outcome randomised controlled trial. All of the children had a hereditary risk of allergic disease. The diagnosis of allergic disease was made during medical assessments at 1 and 3 years of age.

Results: The mean (standard deviation) standardised cord blood 25(OH)D concentration was 57.0 (24.1) nmol/L. The cumulative incidence of eczema to 3 years of age, n = 101/250 (40 %) was associated with standardised cord blood 25(OH)D concentration, with a 10 nmol/L rise in 25(OH)D concentration reducing the risk of eczema by 8 % (relative risk 0.92, 95 % confidence interval 0.86-0.97; P = 0.005). This association was stronger at 1 year of age, when a 10 nmol/L rise in standardised cord blood 25(OH)D concentration reduced the risk of eczema by 12 % (relative risk 0.88, 95 % confidence interval 0.81-0.96; P = 0.002). No associations between cord blood 25(OH)D concentrations and development of allergic sensitisation, allergic rhinitis or asthma in early childhood were found.

Conclusion: In children with a family history of allergic disease, a higher cord blood 25(OH)D concentration appears to be associated with reduced risk of eczema in early childhood.

Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).
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http://dx.doi.org/10.1186/s40413-015-0077-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594897PMC
October 2015

Bias and Precision of the "Multiple Imputation, Then Deletion" Method for Dealing With Missing Outcome Data.

Am J Epidemiol 2015 Sep 2;182(6):528-34. Epub 2015 Sep 2.

Multiple imputation (MI) is increasingly being used to handle missing data in epidemiologic research. When data on both the exposure and the outcome are missing, an alternative to standard MI is the "multiple imputation, then deletion" (MID) method, which involves deleting imputed outcomes prior to analysis. While MID has been shown to provide efficiency gains over standard MI when analysis and imputation models are the same, the performance of MID in the presence of auxiliary variables for the incomplete outcome is not well understood. Using simulated data, we evaluated the performance of standard MI and MID in regression settings where data were missing on both the outcome and the exposure and where an auxiliary variable associated with the incomplete outcome was included in the imputation model. When the auxiliary variable was unrelated to missingness in the outcome, both standard MI and MID produced negligible bias when estimating regression parameters, with standard MI being more efficient in most settings. However, when the auxiliary variable was also associated with missingness in the outcome, alarmingly MID produced markedly biased parameter estimates. On the basis of these results, we recommend that researchers use standard MI rather than MID in the presence of auxiliary variables associated with an incomplete outcome.
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http://dx.doi.org/10.1093/aje/kwv100DOI Listing
September 2015

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

Paediatr Perinat Epidemiol 2015 Nov 1;29(6):567-75. Epub 2015 Sep 1.

MRC Biostatistics Unit, Cambridge, UK.

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.
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http://dx.doi.org/10.1111/ppe.12228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847643PMC
November 2015
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