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1.  Diagnostic accuracy of post-mortem MRI for thoracic abnormalities in fetuses and children 
European Radiology  2014;24(11):2876-2884.
Objectives
To compare the diagnostic accuracy of post-mortem magnetic resonance imaging (PMMR) specifically for non-cardiac thoracic pathology in fetuses and children, compared with conventional autopsy.
Methods
Institutional ethics approval and parental consent was obtained. A total of 400 unselected fetuses and children underwent PMMR before conventional autopsy, reported blinded to the other dataset.
Results
Of 400 non-cardiac thoracic abnormalities, 113 (28 %) were found at autopsy. Overall sensitivity and specificity (95 % confidence interval) of PMMR for any thoracic pathology was poor at 39.6 % (31.0, 48.9) and 85.5 % (80.7, 89.2) respectively, with positive predictive value (PPV) 53.7 % (42.9, 64.0) and negative predictive value (NPV) 77.0 % (71.8, 81.4). Overall agreement was 71.8 % (67.1, 76.2). PMMR was most sensitive at detecting anatomical abnormalities, including pleural effusions and lung or thoracic hypoplasia, but particularly poor at detecting infection.
Conclusions
PMMR currently has relatively poor diagnostic detection rates for the commonest intra-thoracic pathologies identified at autopsy in fetuses and children, including respiratory tract infection and diffuse alveolar haemorrhage. The reasonable NPV suggests that normal thoracic appearances at PMMR exclude the majority of important thoracic lesions at autopsy, and so could be useful in the context of minimally invasive autopsy for detecting non-cardiac thoracic abnormalities.
Key Points
• PMMR has relatively poor diagnostic detection rates for common intrathoracic pathology
• The moderate NPV suggests that normal PMMR appearances exclude most important abnormalities
• Lung sampling at autopsy remains the “gold standard” for pulmonary pathology
doi:10.1007/s00330-014-3313-8
PMCID: PMC4182596  PMID: 25173624
MRI; Autopsy; Pathology; Fetuses; Children
2.  Evaluating bias due to data linkage error in electronic healthcare records 
Background
Linkage of electronic healthcare records is becoming increasingly important for research purposes. However, linkage error due to mis-recorded or missing identifiers can lead to biased results. We evaluated the impact of linkage error on estimated infection rates using two different methods for classifying links: highest-weight (HW) classification using probabilistic match weights and prior-informed imputation (PII) using match probabilities.
Methods
A gold-standard dataset was created through deterministic linkage of unique identifiers in admission data from two hospitals and infection data recorded at the hospital laboratories (original data). Unique identifiers were then removed and data were re-linked by date of birth, sex and Soundex using two classification methods: i) HW classification - accepting the candidate record with the highest weight exceeding a threshold and ii) PII–imputing values from a match probability distribution. To evaluate methods for linking data with different error rates, non-random error and different match rates, we generated simulation data. Each set of simulated files was linked using both classification methods. Infection rates in the linked data were compared with those in the gold-standard data.
Results
In the original gold-standard data, 1496/20924 admissions linked to an infection. In the linked original data, PII provided least biased results: 1481 and 1457 infections (upper/lower thresholds) compared with 1316 and 1287 (HW upper/lower thresholds). In the simulated data, substantial bias (up to 112%) was introduced when linkage error varied by hospital. Bias was also greater when the match rate was low or the identifier error rate was high and in these cases, PII performed better than HW classification at reducing bias due to false-matches.
Conclusions
This study highlights the importance of evaluating the potential impact of linkage error on results. PII can help incorporate linkage uncertainty into analysis and reduce bias due to linkage error, without requiring identifiers.
doi:10.1186/1471-2288-14-36
PMCID: PMC4015706  PMID: 24597489
Data linkage; Routine data; Bias; Electronic health records; Evaluation; Linkage quality
4.  Neonatal Encephalopathic Cerebral Injury in South India Assessed by Perinatal Magnetic Resonance Biomarkers and Early Childhood Neurodevelopmental Outcome 
PLoS ONE  2014;9(2):e87874.
Although brain injury after neonatal encephalopathy has been characterised well in high-income countries, little is known about such injury in low- and middle-income countries. Such injury accounts for an estimated 1 million neonatal deaths per year. We used magnetic resonance (MR) biomarkers to characterise perinatal brain injury, and examined early childhood outcomes in South India.
Methods
We recruited consecutive term or near term infants with evidence of perinatal asphyxia and a Thompson encephalopathy score ≥6 within 6 h of birth, over 6 months. We performed conventional MR imaging, diffusion tensor MR imaging and thalamic proton MR spectroscopy within 3 weeks of birth. We computed group-wise differences in white matter fractional anisotropy (FA) using tract based spatial statistics. We allocated Sarnat encephalopathy stage aged 3 days, and evaluated neurodevelopmental outcomes aged 3½ years using Bayley III.
Results
Of the 54 neonates recruited, Sarnat staging was mild in 30 (56%); moderate in 15 (28%) and severe in 6 (11%), with no encephalopathy in 3 (6%). Six infants died. Of the 48 survivors, 44 had images available for analysis. In these infants, imaging indicated perinatal rather than established antenatal origins to injury. Abnormalities were frequently observed in white matter (n = 40, 91%) and cortex (n = 31, 70%) while only 12 (27%) had abnormal basal ganglia/thalami. Reduced white matter FA was associated with Sarnat stage, deep grey nuclear injury, and MR spectroscopy N-acetylaspartate/choline, but not early Thompson scores. Outcome data were obtained in 44 infants (81%) with 38 (79%) survivors examined aged 3½ years; of these, 16 (42%) had adverse neurodevelopmental outcomes.
Conclusions
No infants had evidence for established brain lesions, suggesting potentially treatable perinatal origins. White matter injury was more common than deep brain nuclei injury. Our results support the need for rigorous evaluation of the efficacy of rescue hypothermic neuroprotection in low- and middle-income countries.
doi:10.1371/journal.pone.0087874
PMCID: PMC3914890  PMID: 24505327
5.  Linkage, Evaluation and Analysis of National Electronic Healthcare Data: Application to Providing Enhanced Blood-Stream Infection Surveillance in Paediatric Intensive Care 
PLoS ONE  2013;8(12):e85278.
Background
Linkage of risk-factor data for blood-stream infection (BSI) in paediatric intensive care (PICU) with bacteraemia surveillance data to monitor risk-adjusted infection rates in PICU is complicated by a lack of unique identifiers and under-ascertainment in the national surveillance system. We linked, evaluated and performed preliminary analyses on these data to provide a practical guide on the steps required to handle linkage of such complex data sources.
Methods
Data on PICU admissions in England and Wales for 2003-2010 were extracted from the Paediatric Intensive Care Audit Network. Records of all positive isolates from blood cultures taken for children <16 years and captured by the national voluntary laboratory surveillance system for 2003-2010 were extracted from the Public Health England database, LabBase2. “Gold-standard” datasets with unique identifiers were obtained directly from three laboratories, containing microbiology reports that were eligible for submission to LabBase2 (defined as “clinically significant” by laboratory microbiologists). Reports in the gold-standard datasets were compared to those in LabBase2 to estimate ascertainment in LabBase2. Linkage evaluated by comparing results from two classification methods (highest-weight classification of match weights and prior-informed imputation using match probabilities) with linked records in the gold-standard data. BSI rate was estimated as the proportion of admissions associated with at least one BSI.
Results
Reporting gaps were identified in 548/2596 lab-months of LabBase2. Ascertainment of clinically significant BSI in the remaining months was approximately 80-95%. Prior-informed imputation provided the least biased estimate of BSI rate (5.8% of admissions). Adjusting for ascertainment, the estimated BSI rate was 6.1-7.3%.
Conclusion
Linkage of PICU admission data with national BSI surveillance provides the opportunity for enhanced surveillance but analyses based on these data need to take account of biases due to ascertainment and linkage error. This study provides a generalisable guide for linkage, evaluation and analysis of complex electronic healthcare data.
doi:10.1371/journal.pone.0085278
PMCID: PMC3869925  PMID: 24376874
6.  Therapeutic Hypothermia for Neonatal Encephalopathy in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(3):e58834.
Although selective or whole body cooling combined with optimal intensive care improves outcomes following neonatal encephalopathy in high-income countries, the safety and efficacy of cooling in low-and middle-income countries is not known.
Objective
We performed a systematic review and meta-analysis of all published randomised or quasi-randomised controlled trials of cooling therapy for neonatal encephalopathy in low-and middle-income countries.
Results
Seven trials, comprising a total of 567 infants were included in the meta-analysis. Most study infants had mild (15%) or moderate encephalopathy (48%) and did not receive invasive ventilation (88%). Cooling devices included water-circulating cooling caps, frozen gel packs, ice, water bottles, and phase-changing material. No statistically significant reduction in neonatal mortality was seen with cooling (risk ratio: 0.74, 95% confidence intervals: 0.44 to 1.25). Data on other neonatal morbidities and long-term neurological outcomes were insufficient.
Conclusion
Cooling therapy was not associated with a statistically significant reduction in neonatal mortality in low-and middle-income countries although the confidence intervals were wide and not incompatible with results seen in high-income countries. The apparent lack of treatment effect may be due to the heterogeneity and poor quality of the included studies, inefficiency of the low technology cooling devices, lack of optimal neonatal intensive care, sedation and ventilatory support, overuse of oxygen, or may be due to the intrinsic difference in the population, for example higher rates of perinatal infection, obstructed labor, intrauterine growth retardation and maternal malnutrition. Evaluation of the safety and efficacy of cooling in adequately powered randomised controlled trials is required before cooling is offered in routine clinical practice in low-and middle-income countries.
doi:10.1371/journal.pone.0058834
PMCID: PMC3602578  PMID: 23527034
7.  Post mortem magnetic resonance imaging in the fetus, infant and child: A comparative study with conventional autopsy (MaRIAS Protocol) 
BMC Pediatrics  2011;11:120.
Background
Minimally invasive autopsy by post mortem magnetic resonance (MR) imaging has been suggested as an alternative for conventional autopsy in view of the declining consented autopsy rates. However, large prospective studies rigorously evaluating the accuracy of such an approach are lacking. We intend to compare the accuracy of a minimally invasive autopsy approach using post mortem MR imaging with that of conventional autopsy in fetuses, newborns and children for detection of the major pathological abnormalities and/or determination of the cause of death.
Methods/Design
We recruited 400 consecutive fetuses, newborns and children referred for conventional autopsy to one of the two participating hospitals over a three-year period. We acquired whole body post mortem MR imaging using a 1.5 T MR scanner (Avanto, Siemens Medical Solutions, Enlargen, Germany) prior to autopsy. The total scan time varied between 90 to 120 minutes. Each MR image was reported by a team of four specialist radiologists (paediatric neuroradiology, paediatric cardiology, paediatric chest & abdominal imaging and musculoskeletal imaging), blinded to the autopsy data. Conventional autopsy was performed according to the guidelines set down by the Royal College of Pathologists (UK) by experienced paediatric or perinatal pathologists, blinded to the MR data. The MR and autopsy data were recorded using predefined categorical variables by an independent person.
Discussion
Using conventional post mortem as the gold standard comparator, the MR images will be assessed for accuracy of the anatomical morphology, associated lesions, clinical usefulness of information and determination of the cause of death. The sensitivities, specificities and predictive values of post mortem MR alone and MR imaging along with other minimally invasive post mortem investigations will be presented for the final diagnosis, broad diagnostic categories and for specific diagnosis of each system.
Clinical Trial Registration
NCT01417962
NIHR Portfolio Number: 6794
doi:10.1186/1471-2431-11-120
PMCID: PMC3259035  PMID: 22192497
Autopsy; post mortem magnetic resonance imaging; stillbirth; sudden infant death; diagnostic study; minimally invasive autopsy
8.  Implementing and Disseminating an Evidence-Based Program to Prevent Falls in Older Adults, Texas, 2007-2009 
Preventing Chronic Disease  2010;7(6):A130.
Introduction
Falls are a public health problem for the growing population of older adults. We describe a statewide effort to implement and disseminate A Matter of Balance/Volunteer Lay Leader model, an evidence-based fall-prevention program.
Methods
We analyzed 2 secondary databases: 1) a centralized administrative data set to document implementation processes and structures for delivering the program and 2) a common set of outcome measures for assessing the effect of the program on older Texans. We used multivariate analyses to examine changes on key outcome variables, controlling for major covariates.
Results
From 2007 through 2009, we reached 3,092 older Texas residents. Program capacity was built by certifying 98 master trainers and 402 lay leaders and delivering the program in 227 classes through the Area Agency on Aging network. Immediate outcome results were positive, which indicates a pathway to promote more successful aging: 1) increases in falls efficacy, 2) improvements in overall physical activity levels, and 3) reductions in interference with everyday normal routines.
Conclusion
Widespread dissemination of a program to prevent falls can promote active aging among people who would otherwise be at risk for a downward cycle of health and functionality. Creating partnerships among different delivery sectors is needed for building community infrastructure to enhance the health of older adults.
PMCID: PMC2995605  PMID: 20950537
9.  Early detection of cystic fibrosis lung disease: multiple‐breath washout versus raised volume tests 
Thorax  2007;62(4):341-347.
Background
Lung clearance index (LCI), a measure of ventilation inhomogeneity derived from the multiple‐breath inert gas washout (MBW) technique, has been shown to detect abnormal lung function more readily than spirometry in preschool children with cystic fibrosis, but whether this holds true during infancy is unknown.
Objectives
To compare the extent to which parameters derived from the MBW and the raised lung volume rapid thoraco–abdominal compression (RVRTC) techniques identify diminished airway function in infants with cystic fibrosis when compared with healthy controls.
Methods
Measurements were performed during quiet sleep, with the tidal breathing MBW technique being performed before the forced expiratory manoeuvres.
Results
Measurements were obtained in 39 infants with cystic fibrosis (mean (SD) age 41.4 (22.0) weeks) and 21 controls (37.0 (15.1) weeks). Infants with cystic fibrosis had a significantly higher respiratory rate (38 (10) vs 32 (5) bpm) and LCI (8.4 (1.5) vs 7.2 (0.3)), and significantly lower values for all forced expiratory flow‐volume parameters compared with controls. Girls with cystic fibrosis had significantly lower forced expiratory volume (FEV0.5 and FEF25–75 ) than boys (mean (95% CI girls–boys): –1.2 (–2.1 to −0.3) for FEV0.5 Z score; FEF25–75: –1.2 (–2.2 to −0.15)). When using both the MBW and RVRTC techniques, abnormalities were detected in 72% of the infants with cystic fibrosis, with abnormalities detected in 41% using both techniques and a further 15% by each of the two tests performed.
Conclusions
These findings support the view that inflammatory and/or structural changes in the airways of children with cystic fibrosis start early in life, and have important implications regarding early detection and interventions. Monitoring of early lung disease and functional status in infants and young children with cystic fibrosis may be enhanced by using both MBW and the RVRTC.
doi:10.1136/thx.2006.068262
PMCID: PMC2092467  PMID: 17121870
LCI; lung clearance index; MBW; multiple‐breath wash out; RVRTC; raised lung volume rapid thoraco–abdominal compression; FEV, forced expiratory volume
10.  Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study 
Lancet Neurology  2008;7(8):696-703.
Summary
Background
Episodes of childhood convulsive status epilepticus (CSE) commonly start in the community. Treatment of CSE aims to minimise the length of seizures, treat the causes, and reduce adverse outcomes; however, there is a paucity of data on the treatment of childhood CSE. We report the findings from a systematic, population-based study on the treatment of community-onset childhood CSE.
Methods
We collected data prospectively on children in north London, UK, who had episodes of CSE (ascertainment 62–84%). The factors associated with seizure termination after first-line and second-line therapies, episodes of CSE lasting for longer than 60 min, and respiratory depression were analysed with logistic regression. Analysis was per protocol, and adjustment was made for repeat episodes in individuals.
Results
182 children of median age 3·24 years (range 0·16–15·98 years) were included in the North London Convulsive Status Epilepticus in Childhood Surveillance Study (NLSTEPSS) between May, 2002, and April, 2004. 61% (147) of 240 episodes were treated prehospital, of which 32 (22%) episodes were terminated. Analysis with multivariable models showed that treatment with intravenous lorazepam (n=107) in the accident and emergency department was associated with a 3·7 times (95% CI 1·7–7·9) greater likelihood of seizure termination than was treatment with rectal diazepam (n=80). Treatment with intravenous phenytoin (n=32) as a second-line therapy was associated with a 9 times (95% CI 3–27) greater likelihood of seizure termination than was treatment with rectal paraldehyde (n=42). No treatment prehospital (odds ratio [OR] 2·4, 95% CI 1·2–4·5) and more than two doses of benzodiazepines (OR 3·6, 1·9–6·7) were associated with episodes that lasted for more than 60 min. Treatment with more than two doses of benzodiazepines was associated with respiratory depression (OR 2·9, 1·4–6·1). Children with intermittent CSE arrived at the accident and emergency department later after seizure onset than children with continuous CSE did (median 45 min [range 11–514 min] vs 30 min [5–90 min]; p<0·0001, Mann-Whitney U test); for each minute delay from onset of CSE to arrival at the accident and emergency department there was a 5% cumulative increase in the risk of the episode lasting more than 60 min.
Interpretation
These data add to the debate on optimum emergency treatment of childhood CSE and suggest that the current guidelines could be updated.
Funding
An anonymous donor to UCL Institute of Child Health; the Wellcome Trust; UK Department of Health National Institute for Health Research Biomedical Research Centres Funding Scheme; Medical Research Council.
doi:10.1016/S1474-4422(08)70141-8
PMCID: PMC2467454  PMID: 18602345
11.  Reference Ranges for Spirometry Across All Ages 
Rationale: The Third National Health and Nutrition Examination Survey (NHANES III) reference is currently recommended for interpreting spirometry results, but it is limited by the lack of subjects younger than 8 years and does not continuously model spirometry across all ages.
Objectives: By collating pediatric data from other large-population surveys, we have investigated ways of developing reference ranges that more accurately describe the relationship between spirometric lung function and height and age within the pediatric age range, and allow a seamless transition to adulthood.
Methods: Data were obtained from four surveys and included 3,598 subjects aged 4–80 years. The original analyses were sex specific and limited to non-Hispanic white subjects. An extension of the LMS (lambda, mu, sigma) method, widely used to construct growth reference charts, was applied.
Measurements and Main Results: The extended models have four important advantages over the original NHANES III analysis as follows: (1) they extend the reference data down to 4 years of age, (2) they incorporate the relationship between height and age in a way that is biologically plausible, (3) they provide smoothly changing curves to describe the transition between childhood and adulthood, and (4) they highlight the fact that the range of normal values is highly dependent on age.
Conclusions: The modeling technique provides an elegant solution to a complex and longstanding problem. Furthermore, it provides a biologically plausible and statistically robust means of developing continuous reference ranges from early childhood to old age. These dynamic models provide a platform from which future studies can be developed to continue to improve the accuracy of reference data for pulmonary function tests.
doi:10.1164/rccm.200708-1248OC
PMCID: PMC2643211  PMID: 18006882
spirometry; pulmonary function; reference values
12.  Behaviour change in perinatal care practices among rural women exposed to a women's group intervention in Nepal [ISRCTN31137309] 
Background
A randomised controlled trial of participatory women's groups in rural Nepal previously showed reductions in maternal and newborn mortality. In addition to the outcome data we also collected previously unreported information from the subgroup of women who had been pregnant prior to study commencement and conceived during the trial period. To determine the mechanisms via which the intervention worked we here examine the changes in perinatal care of these women. In particular we use the information to study factors affecting positive behaviour change in pregnancy, childbirth and newborn care.
Methods
Women's groups focusing on perinatal care were introduced into 12 of 24 study clusters (average cluster population 7000). A total of 5400 women of reproductive age enrolled in the trial had previously been pregnant and conceived during the trial period.
For each of four outcomes (attendance at antenatal care; use of a boiled blade to cut the cord; appropriate dressing of the cord; not discarding colostrum) each of these women was classified as BETTER, GOOD, BAD or WORSE to describe whether and how she changed her pre-trial practice. Multilevel multinomial models were used to identify women most responsive to intervention.
Results
Among those not initially following good practice, women in intervention areas were significantly more likely to do so later for all four outcomes (OR 1.92 to 3.13). Within intervention clusters, women who attended groups were more likely to show a positive change than non-group members with regard to antenatal care utilisation and not discarding colostrum, but non-group members also benefited.
Conclusion
Women's groups promoted significant behaviour change for perinatal care amongst women not previously following good practice. Positive changes attributable to intervention were not restricted to specific demographic subgroups.
doi:10.1186/1471-2393-6-20
PMCID: PMC1513253  PMID: 16776818
13.  An investigation of minimisation criteria 
Background
Minimisation can be used within treatment trials to ensure that prognostic factors are evenly distributed between treatment groups. The technique is relatively straightforward to apply but does require running tallies of patient recruitments to be made and some simple calculations to be performed prior to each allocation. As computing facilities have become more widely available, minimisation has become a more feasible option for many. Although the technique has increased in popularity, the mode of application is often poorly reported and the choice of input parameters not justified in any logical way.
Methods
We developed an automated package for patient allocation which incorporated a simulation arm. We here demonstrate how simulation of data can help to determine the input parameters to be used in a subsequent application of minimisation.
Results
Several scenarios were simulated. Within the selected scenarios, increasing the number of factors did not substantially adversely affect the extent to which the treatment groups were balanced with respect to the prognostic factors. Weighting of the factors tended to improve the balance when factors had many categories with only a slight negative effect on the factors with fewer categories. When interactions between factors were included as minimisation factors, there was no major reduction in the balance overall.
Conclusion
With the advent of widely available computing facilities, researchers can be better equipped to implement minimisation as a means of patient allocation. Simulations prior to study commencement can assist in the choice of minimisation parameters and can be used to justify those selections.
doi:10.1186/1471-2288-6-11
PMCID: PMC1431552  PMID: 16539715
14.  Incidence of fires and related injuries after giving out free smoke alarms: cluster randomised controlled trial 
BMJ : British Medical Journal  2002;325(7371):995.
Objective
To measure the effect of giving out free smoke alarms on rates of fires and rates of fire related injury in a deprived multiethnic urban population.
Design
Cluster randomised controlled trial.
Setting
Forty electoral wards in two boroughs of inner London, United Kingdom.
Participants
Primarily households including elderly people or children and households that are in housing rented from the borough council.
Intervention
20 050 smoke alarms, fittings, and educational brochures distributed free and installed on request.
Main outcome measures
Rates of fires and related injuries during two years after the distribution; alarm ownership, installation, and function.
Results
Giving out free smoke alarms did not reduce injuries related to fire (rate ratio 1.3; 95% confidence interval 0.9 to 1.9), admissions to hospital and deaths (1.3; 0.7 to 2.3), or fires attended by the fire brigade (1.1; 0.96 to 1.3). Similar proportions of intervention and control households had installed alarms (36/119 (30%) v 35/109 (32%); odds ratio 0.9; 95% confidence interval 0.5 to 1.7) and working alarms (19/118 (16%) v 18/108 (17%); 0.9; 0.4 to 1.8).
Conclusions
Giving out free smoke alarms in a deprived, multiethnic, urban community did not reduce injuries related to fire, mostly because few alarms had been installed or were maintained.
What is already known on this topicIn the United Kingdom, residential fires caused 466 deaths and 14 600 non-fatal injuries in 1999The risk of death from fire is associated with socioeconomic classOne study reported an 80% decline in hospitalisations and deaths from residential fires after free smoke alarms were distributed in an area at high risk, but these results may not apply in other settings, and evidence from randomised controlled trials is lackingWhat this study addsGiving out free smoke alarms in a multiethnic poor urban population did not reduce injuries related to fire or firesGiving smoke alarms away may be a waste of resources and of little benefit unless alarm installation and maintenance is assured
PMCID: PMC131023  PMID: 12411355
15.  Screening of newborn infants for cholestatic hepatobiliary disease with tandem mass spectrometry 
BMJ : British Medical Journal  1999;319(7208):471-477.
Objective
To assess the feasibility of screening for cholestatic hepatobiliary disease and extrahepatic biliary atresia by using tandem mass spectrometry to measure conjugated bile acids in dried blood spots obtained from newborn infants at 7-10 days of age for the Guthrie test.
Setting
Three tertiary referral clinics and regional neonatal screening laboratories.
Design
Unused blood spots from the Guthrie test were retrieved for infants presenting with cholestatic hepatobiliary disease and from the two cards stored on either side of each card from an index child. Concentrations of conjugated bile acids measured by tandem mass spectrometry in the two groups were compared.
Main outcome measures
Concentrations of glycodihydroxycholanoates, glycotrihydroxycholanoates, taurodihydroxycholanoates, and taurotrihydroxycholanoates. Receiver operator curves were plotted to determine which parameter (or combination of parameters) would best predict the cases of cholestatic hepatobiliary disease and extrahepatic biliary atresia. The sensitivity and specificity at a selection of cut off values for each bile acid species and for total bile acid concentrations for the detection of the two conditions were calculated.
Results
218 children with cholestatic hepatobiliary disease were eligible for inclusion in the study. Two children without a final diagnosis and five who presented at <14 days of age were excluded. Usable blood spots were obtained from 177 index children and 708 comparison children. Mean concentrations of all four bile acid species were significantly raised in children with cholestatic hepatobiliary disease and extrahepatic biliary atresia compared with the unaffected children (P<0.0001). Of 177 children with cholestatic hepatobiliary disease, 104 (59%) had a total bile acid concentration >33 μmol/l (97.5th centile value for comparison group). Of the 61 with extrahepatic biliary atresia, 47 (77%) had total bile acid concentrations >33 μmol/l. Taurotrihydroxycholanoate and total bile acid concentrations were the best predictors of both conditions. For all cholestatic hepatobiliary disease, a cut off level of total bile acid concentration of 30 μmol/l gave a sensitivity of 62% and a specificity of 96%, while the corresponding values for extrahepatic biliary atresia were 79% and 96%.
Conclusion
Most children who present with extrahepatic biliary atresia and other forms of cholestatic hepatobiliary disease have significantly raised concentrations of conjugated bile acids as measured by tandem mass spectrometry at the time when samples are taken for the Guthrie test. Unfortunately the separation between the concentrations in these infants and those in the general population is not sufficient to make mass screening for cholestatic hepatobiliary disease a feasible option with this method alone.
Key messagesThe prognosis of cholestatic hepatobiliary disease in infancy, in particular biliary atresia, is improved by early detectionInfants destined to present with cholestatic jaundice in the first few months of life have raised concentrations of bile acids in the blood spots obtained at 7-10 days for current neonatal screening programmesTandem mass spectrometry can be used to detect this marker of neonatal cholestasisUnfortunately there is too much overlap between bile acid concentrations in infants with cholestasis and those in control infants for this to be used as a single screening test for cholestatic hepatobiliary disease in general and biliary atresiaTandem mass spectrometry is a powerful tool for neonatal screening but every potential application must be carefully assessed
PMCID: PMC28198  PMID: 10454398
16.  Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age? 
Thorax  2013;69(4):320-327.
Rationale
Sensitive outcome measures applicable in different centres to quantify and track early pulmonary abnormalities in infants with cystic fibrosis (CF) are needed both for clinical care and interventional trials. Chest CT has been advocated as such a measure yet there is no validated scoring system in infants.
Objectives
The objectives of this study were to standardise CT data collection across multiple sites; ascertain the incidence of bronchial dilatation and air trapping in newborn screened (NBS) infants with CF at 1 year; and assess the reproducibility of Brody-II, the most widely used scoring system in children with CF, during infancy.
Methods
A multicentre observational study of early pulmonary lung disease in NBS infants with CF at age 1 year using volume-controlled chest CT performed under general anaesthetic.
Main results
65 infants with NBS-diagnosed CF had chest CT in three centres. Small insignificant variations in lung recruitment manoeuvres but significant centre differences in radiation exposures were found. Despite experienced scorers and prior training, with the exception of air trapping, inter- and intraobserver agreement on Brody-II score was poor to fair (eg, interobserver total score mean (95% CI) κ coefficient: 0.34 (0.20 to 0.49)). Only 7 (11%) infants had a total CT score ≥12 (ie, ≥5% maximum possible) by either scorer.
Conclusions
In NBS infants with CF, CT changes were very mild at 1 year, and assessment of air trapping was the only reproducible outcome. CT is thus of questionable value in infants of this age, unless an improved scoring system for use in mild CF disease can be developed.
doi:10.1136/thoraxjnl-2013-204176
PMCID: PMC3963531  PMID: 24132911
17.  Patient-reported quality of life outcomes for children with serious congenital heart defects 
Archives of Disease in Childhood  2014;99(5):413-419.
Objective
To compare patient-reported, health-related quality of life (QoL) for children with serious congenital heart defects (CHDs) and unaffected classmates and to investigate the demographic and clinical factors influencing QoL.
Design
Retrospective cohort study.
Setting
UK National Health Service.
Patients
UK-wide cohort of children with serious CHDs aged 10–14 years requiring cardiac intervention in the first year of life in one of 17 UK paediatric cardiac surgical centres operating during 1992–1995. A comparison group of classmates of similar age and sex was recruited.
Main outcome measures
Child self-report of health-related QoL scores (Pediatric Quality of Life Inventory, PedsQL) and parental report of schooling and social activities.
Results
Questionnaires were completed by 477 children with CHDs (56% boys; mean age 12.1 (SD 1.0) years) and 464 classmates (55%; 12.0 (SD 1.1) years). Children with CHDs rated QoL significantly lower than classmates (CHDs: median 78.3 (IQR 65.0–88.6); classmates: 88.0 (80.2–94.6)) and scored lower on physical (CHDs: 84.4; classmates: 93.8; difference 9.4 (7.8 to 10.9)) and psychosocial functioning subscales (CHDs: 76.7, classmates: 85.0; difference 8.3 (6.0 to 10.6)). Cardiac interventions, school absence, regular medications and non-cardiac comorbidities were independently associated with reduced QoL. Participation in sport positively influenced QoL and was associated with higher psychosocial functioning scores.
Conclusions
Children with serious CHDs experience lower QoL than unaffected classmates. This appears related to the burden of clinical intervention rather than underlying cardiac diagnosis. Participation in sports activities is positively associated with increased emotional well-being. Child self-report measures of QoL would be a valuable addition to clinical outcome audit in this age group.
doi:10.1136/archdischild-2013-305130
PMCID: PMC3995241  PMID: 24406805
18.  Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants 
Thorax  2013;69(10):910-917.
Rationale
Newborn screening (NBS) for cystic fibrosis (CF) allows early intervention. Design of randomised controlled trials (RCT) is currently impeded by uncertainty regarding evolution of lung function, an important trial end point in such infants.
Objective
To assess changes in pulmonary function during the first year of life in CF NBS infants.
Methods
Observational longitudinal study. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV0.5) were measured at 3 months and 1 year of age.
Main results
Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year.
Conclusions
This is the first study reporting improvements in FEV0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs.
doi:10.1136/thoraxjnl-2013-204023
PMCID: PMC4174068  PMID: 24072358
Cystic Fibrosis; Lung Physiology; Paediatric Lung Disaese

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