Analysis of paediatric visual acuity using Bayesian copula models with sinh-arcsinh marginal densities.

We analyse paediatric ophthalmic data from a large sample of children aged between 3 and 8 years. We use a Bayesian additive conditional bivariate copula regression model with sinh-arcsinh marginal densities with location, scale, and shape parameters that depend smoothly on a covariate. We perform Bayesian inference about the unknown quantities of our model using a specially tailored Markov chain Monte Carlo algorithm. We gain new insights about the processes, which determine transformations in visual acuity with respect to age, including the nature of joint changes in both eyes as modelled with the age-related copula dependence parameter. We analyse posterior predictive distributions to identify children with unusual sight characteristics, distinguishing those who are bivariate, but not univariate outliers. In this way, we provide an innovative tool that enables clinicians to identify children with unusual sight who may otherwise be missed. We compare our simultaneous Bayesian method with a two-step frequentist generalised additive modelling approach.

Childhood medulloblastoma-a single institution's historical perspective on survival and functional morbidity.

PURPOSE: To compare results from a third (1995-2010) cohort of children with medulloblastoma with two previous series (J Neurosurg 86:13-21, 1997; Arch Dis Child 54:200-203, 1979) to analyse the effects of management changes aimed at improving both overall and event-free survivals (OS and EFS) and functional outcomes. METHODS: Review of neuro-oncology and imaging databases and previously published results. RESULTS: There was no statistically significant improvement in the 5-year OS for 104 children diagnosed 1995-2010, 61.5% (95% CI, 52.9, 71.6), compared with 50% of the 80 children presenting 1980-1990 (J Neurosurg 86:13-21, 1997) (difference 11.5%; 95% CI, 2.8, 25.4). Five-year OS for 96 children suitable for risk-stratification was overall 66% (95% CI, 57.9, 75.8); standard risk 77.8% (95% CI, 67.4, 89.7); high risk < 3 years 50.0% (95% CI, 32.3, 77.5); high risk ≥ 3 years 54.5% (95% CI, 37.2, 79.9); 5-year EFS were standard risk 68.5% (95% CI, 57.2, 82.1); high risk < 3 years 40.0% (95% CI, 23.4, 68.4); and high risk ≥ 3 years 36.4% (95% CI, 20.9, 63.2); overall 55.2% (95% CI, 46.1, 66.1). Of 62/63 ≥ 5-year survivor, 9 died later from tumour relapse and 4 from second malignancy. Functional outcomes of 62 of the 63 ≥ 5-year survivors: 67.7% had educational issues requiring remedial input; 18% restricted mobility indoors and outdoors; 59.7% hearing impairment (42% prescribed aids). CONCLUSIONS: 1. Comparison of this single-institution series with its predecessor found that revised chemotherapy and RT protocols and greater accuracy of risk stratification did not result in statistically significant improvements in either survival or treatment-related functional disability. 2. Extended (> 5-year) follow-up is essential if 20% of late deaths from relapse and second malignancies are not to be overlooked.

Pulmonary function deficits in newborn screened infants with cystic fibrosis managed with standard UK care are mild and transient.

With the advent of novel designer molecules for cystic fibrosis (CF) treatment, there is huge need for early-life clinical trial outcomes, such as infant lung function (ILF). We investigated the degree and tracking of ILF abnormality during the first 2 years of life in CF newborn screened infants.Forced expiratory volume in 0.5 s (FEV0.5), lung clearance index (LCI) and plethysmographic functional residual capacity were measured at ∼3 months, 1 year and 2 years in 62 infants with CF and 34 controls.By 2 years there was no significant difference in FEV0.5 z-score between CF and controls, whereas mean LCI z-score was 0.81 (95% CI 0.45-1.17) higher in CF. However, there was no significant association between LCI z-score at 2 years with either 3-month or 1-year results. Despite minimal average group changes in any ILF outcome during the second year of life, marked within-subject changes occurred. No child had abnormal LCI or FEV0.5 on all test occasions, precluding the ability to identify "high-risk" infants in early life.In conclusion, changes in lung function are mild and transient during the first 2 years of life in newborn screened infants with CF when managed according to a standardised UK treatment protocol. Their potential role in tracking disease to later childhood will be ascertained by ongoing follow-up.

Natural variability of lung function in young healthy school children.

Knowledge about long-term variability of lung function in healthy children is essential when monitoring and treating those with respiratory disease over time. The aim of this study was to define the natural variability in spirometry in young children after an interval of 12 months.The Size and Lung function In Children study was a prospective study designed to assess spirometry and body size, shape and composition in a multi-ethnic population of London school children. 14 schools with a wide range of socioeconomic circumstances were recruited. Spirometric and anthropometric assessments and parental questionnaires pertaining to respiratory symptoms, previous medical history, pubertal status and socioeconomic circumstances were completed at baseline and ∼1 year later.Technically acceptable spirometry data on two occasions ∼1 year apart (range 9-16 months) were available in 758 children (39% boys, mean±sd age 8.1±1.6 years), 593 of whom were classified as "healthy". Mean±sd within-subject between-test variability was 0.05±0.6 z-scores, with 95% of all the children achieving a between-test variability within ±1.2 z-scores (equating to ∼13% predicted).Natural variations of up to 1.2 z-scores occur in healthy children over ∼1 year. These must be considered when interpreting results from annual reviews in those with lung disease who are otherwise stable, if unnecessary further investigations or changes in treatment are to be avoided.

Effects of dietary nitrate supplementation on symptoms of acute mountain sickness and basic physiological responses in a group of male adolescents during ascent to Mount Everest Base Camp.

The purpose of this study was to investigate the effects of dietary nitrate supplementation, in the form of beetroot juice, on acute mountain sickness (AMS) symptoms and physiological responses, in a group of young males trekking to Mount Everest Base Camp (EBC). Forty healthy male students (mean age (SD): 16 (1) yrs) trekked to EBC over 11 days. Following an overnight fast, each morning participants completed the Lake Louise AMS questionnaire and underwent a series of physiological tests: resting blood pressure as well as resting and exercising heart rate, respiratory rate, and peripheral oxygen saturation. The exercise test consisted of a standardised 2-min stepping protocol and measurements were taken in the last 10 s. Participants in the intervention arm of the study consumed 140 ml of concentrated beetroot juice daily, containing approximately 10 mmol of nitrate, while those in the control arm consumed 140 ml of concentrated blackcurrant cordial with negligible nitrate content. Drinks were taken for the first seven days at high altitude (days 2-8), in two equal doses; one with breakfast, and one with the evening meal. Mixed modelling revealed no significant between-groups difference in the incidence of AMS (Odds Ratio - nitrate vs. CONTROL: 1.16 (95% CI: 0.59; 2.29)). Physiological changes occurring during ascent to high altitude generally were not significantly different between the two groups (Model Coef (95% CI) - average difference nitrate vs. CONTROL: systolic blood pressure, 0.16 (-4.47; 4.79); peripheral oxygen saturation, 0.28 (-0.85; 1.41); heart rate, -0.48 (-8.47; 7.50) (Model Coef (95% CI) - relative difference nitrate vs. CONTROL: ventilatory rate, 0.95 (0.82; 1.08)). Modelling revealed that diastolic blood pressure was 3.37 mmHg (0.24; 6.49) higher for participants in the beetroot juice, however this difference was no larger than that found at baseline and no interaction effect was observed. Supplementation with dietary nitrate did not significantly change symptoms of AMS or alter key physiological variables, in a group of adolescent males during a high altitude trekking expedition. There was no evidence of harm from dietary nitrate supplementation in this context. Given the wide confidence intervals in all models, a larger sample size would be required to exclude a false negative result. Our data suggest that prolonged oral nitrate supplementation is safe and feasible at altitude but has little physiological or clinical effect.

Comparison of diagnostic performance for perinatal and paediatric post-mortem imaging: CT versus MRI.

OBJECTIVES: To compare the diagnostic yield of whole-body post-mortem computed tomography (PMCT) imaging to post-mortem magnetic resonance (PMMR) imaging in a prospective study of fetuses and children. METHODS: We compared PMCT and PMMR to conventional autopsy as the gold standard for the detection of (a) major pathological abnormalities related to the cause of death and (b) all diagnostic findings in five different body organ systems. RESULTS: Eighty two cases (53 fetuses and 29 children) underwent PMCT and PMMR prior to autopsy, at which 55 major abnormalities were identified. Significantly more PMCT than PMMR examinations were non-diagnostic (18/82 vs. 4/82; 21.9 % vs. 4.9 %, diff 17.1 % (95 % CI 6.7, 27.6; p < 0.05)). PMMR gave an accurate diagnosis in 24/55 (43.64 %; 95 % CI 31.37, 56.73 %) compared to 18/55 PMCT (32.73 %; 95 % CI 21.81, 45.90). PMCT was particularly poor in fetuses <24 weeks, with 28.6 % (8.1, 46.4 %) more non-diagnostic scans. Where both PMCT and PMMR were diagnostic, PMMR gave slightly higher diagnostic accuracy than PMCT (62.8 % vs. 59.4 %). CONCLUSION: Unenhanced PMCT has limited value in detection of major pathology primarily because of poor-quality, non-diagnostic fetal images. On this basis, PMMR should be the modality of choice for non-invasive PM imaging in fetuses and children. KEY POINTS: • Overall 17.1 % more PMCT examinations than PMMR were non-diagnostic • 28.6 % more PMCT were non-diagnostic than PMMR in fetuses <24 weeks • PMMR detected almost a third more pathological abnormalities than PMCT • PMMR gave slightly higher diagnostic accuracy when both were diagnostic.

Postmortem cardiovascular magnetic resonance imaging in fetuses and children: a masked comparison study with conventional autopsy.

BACKGROUND: Perinatal and pediatric autopsies have declined worldwide in the past decade. We compared the diagnostic accuracy of postmortem, cardiovascular magnetic resonance (CMR) imaging with conventional autopsy and histopathology assessment in fetuses and children. METHODS AND RESULTS: We performed postmortem magnetic resonance imaging in 400 fetuses and children, using a 1.5-T Siemens Avanto magnetic resonance scanner before conventional autopsy. A pediatric CMR imager reported the CMR images, masked to autopsy information. The pathologists were masked to the information from CMR images. The institutional research ethics committee approved the study, and parental consent was obtained. Assuming a diagnostic accuracy of 50%, 400 cases were required for a 5% precision of estimate. Three cases were excluded from analysis, 2 with no conventional autopsy performed and 1 with insufficient CMR sequences performed. Thirty-eight CMR data sets were nondiagnostic (37 in fetuses ≤24 weeks; 1 in a fetus >24 weeks). In the remaining 359 cases, 44 cardiac abnormalities were noted at autopsy. Overall sensitivity and specificity (95% confidence interval) of CMR was 72.7% (58.2-83.7%) and 96.2% (93.5-97.8%) for detecting any cardiac pathology, with positive and negative predictive values of 72.7% (58.2-83.7%) and 96.2% (93.5-97.8%), respectively. Higher sensitivity of 92.6% (76.6-97.9%), specificity of 99.1% (97.4-99.7%), positive predictive value of 89.3% (72.8-96.3%), and negative predictive value of 99.4% (97.8-99.8%) were seen for major structural heart disease. CONCLUSIONS: Postmortem CMR imaging may be a useful alternative to conventional cardiac autopsy in fetuses and children for detecting cardiac abnormalities. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01417962.

Lung function in children in relation to ethnicity, physique and socioeconomic factors.

Can ethnic differences in spirometry be attributed to differences in physique and socioeconomic factors?Assessments were undertaken in 2171 London primary schoolchildren on two occasions 1 year apart, whenever possible, as part of the Size and Lung function In Children (SLIC) study. Measurements included spirometry, detailed anthropometry, three-dimensional photonic scanning for regional body shape, body composition, information on ethnic ancestry, birth and respiratory history, socioeconomic circumstances, and tobacco smoke exposure.Technically acceptable spirometry was obtained from 1901 children (mean (range) age 8.3 (5.2-11.8) years, 46% boys, 35% White, 29% Black-African origin, 24% South-Asian, 12% Other/mixed) on 2767 test occasions. After adjusting for sex, age and height, forced expiratory volume in 1 s was 1.32, 0.89 and 0.51 z-score units lower in Black-African origin, South-Asian and Other/mixed ethnicity children, respectively, when compared with White children, with similar decrements for forced vital capacity (p<0.001 for all). Although further adjustment for sitting height and chest width reduced differences attributable to ethnicity by up to 16%, significant differences persisted after adjusting for all potential determinants, including socioeconomic circumstances.Ethnic differences in spirometric lung function persist despite adjusting for a wide range of potential determinants, including body physique and socioeconomic circumstances, emphasising the need to use ethnic-specific equations when interpreting results.

Monitoring quality of care through linkage of administrative data: national trends in bloodstream infection in U.K. PICUs 2003-2012.

OBJECTIVES: Interventions to reduce hospital-acquired bloodstream infection have succeeded in reducing rates in U.S. PICUs, but there is a lack of evidence for the impact of similar interventions in the United Kingdom. We assessed variation in bloodstream infection rates within and between PICUs over a 10-year period, during which time infection control strategies (care bundles) were implemented. DESIGN: Observational study linking laboratory data to national audit data of pediatric intensive care admissions (Paediatric Intensive Care Audit Network). SETTING: Twenty PICUs in England and Wales, 2003-2012. PATIENTS: One hundred and two thousand nine hundred ninety-nine children less than 16 years. INTERVENTIONS: Implementation of infection control strategies in PICU captured through a survey of clinicians. MEASUREMENTS AND MAIN RESULTS: Rates of bloodstream infection per 1,000 bed-days were estimated from samples taken between 2 days after admission and up to 2 days following discharge from PICU. Two percent of children experienced at least one bloodstream infection, corresponding to 5.11 (95% CI, 4.90-5.31) per 1,000 bed-days. There was a significant difference in trends preimplementation of infection control strategies (annual decrease of 8.0%; 95% CI, 6.3-9.7%) versus postimplementation (annual decrease of 13.4%; 95% CI, 10.3-16.4%). By 24 months postimplementation, the rate of bloodstream infection had fallen 25.5% and was 15.1% lower than would have been expected if preimplementation trends had continued. CONCLUSIONS: Our population-based study of PICUs in England and Wales demonstrates a steady decline in bloodstream infection rates over time. In addition, there was a significant and incremental further decrease in rates associated with timing of implementation of infection control strategies. Assessment of bloodstream infection trends before as well as after implementation of infection control strategies can be facilitated using data linkage and is important to avoid overestimating the impact of unit-level interventions to improve infection control. Advances in collection and linkage of real-time data could further support quality improvement efforts.

Post-mortem MRI versus conventional autopsy in fetuses and children: a prospective validation study.

BACKGROUND: Post-mortem MRI is a potential diagnostic alternative to conventional autopsy, but few large prospective studies have compared its accuracy with that of conventional autopsy. We assessed the accuracy of whole-body, post-mortem MRI for detection of major pathological lesions associated with death in a prospective cohort of fetuses and children. METHODS: In this prospective validation study, we did pre-autopsy, post-mortem, whole-body MRI at 1·5 T in an unselected population of fetuses (≤24 weeks' or >24 weeks' gestation) and children (aged <16 years) at two UK centres in London between March 1, 2007 and Sept 30, 2011. With conventional autopsy as the diagnostic gold standard, we assessed MRI findings alone, or in conjunction with other minimally invasive post-mortem investigations (minimally invasive autopsy), for accuracy in detection of cause of death or major pathological abnormalities. A radiologist and pathologist who were masked to the autopsy findings indicated whether the minimally invasive autopsy would have been adequate. The primary outcome was concordance rate between minimally invasive and conventional autopsy. FINDINGS: We analysed 400 cases, of which 277 (69%) were fetuses and 123 (31%) were children. Cause of death or major pathological lesion detected by minimally invasive autopsy was concordant with conventional autopsy in 357 (89·3%, 95% CI 85·8-91·9) cases: 175 (94·6%, 90·3-97·0) of 185 fetuses at 24 weeks' gestation or less, 88 (95·7%, 89·3-98·3) of 92 fetuses at more than 24 weeks' gestation, 34 (81·0%, 66·7-90·0) [corrected] of 42 newborns aged 1 month or younger, 45 (84·9%, 72·9-92·1) of 53 infants aged older than 1 month to 1 year or younger, and 15 (53·6%, 35·8-70·5) of 28 children aged older than 1 year to 16 years or younger. The dedicated radiologist or pathologist review of the minimally invasive autopsy showed that in 165 (41%) cases a full autopsy might not have been needed; in these cases, concordance between autopsy and minimally invasive autopsy was 99·4% (96·6-99·9). INTERPRETATION: Minimally invasive autopsy has accuracy similar to that of conventional autopsy for detection of cause of death or major pathological abnormality after death in fetuses, newborns, and infants, but was less accurate in older children. If undertaken jointly by pathologists and radiologists, minimally invasive autopsy could be an acceptable alternative to conventional autopsy in selected cases. FUNDING: Policy research Programme, Department of Health, UK.

Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants.

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.

Is chest CT useful in newborn screened infants with cystic fibrosis at 1 year of age?

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.

Diagnostic accuracy of post-mortem MRI for thoracic abnormalities in fetuses and children.

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.

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.

Diagnostic accuracy of postmortem MRI for musculoskeletal abnormalities in fetuses and children.

OBJECTIVES: The aim of this study was to compare the diagnostic accuracy of postmortem magnetic resonance (PMMR) imaging specifically for musculoskeletal pathology in fetuses and children, compared with conventional autopsy, with radiographic and histopathology assessment. METHODS: Institutional ethics approval and parental consent was obtained. A total of 400 cases underwent PMMR using a 1.5 T Siemens Avanto MR scanner before conventional autopsy. PMMR images and autopsy findings were reported blinded to the other data, respectively. RESULTS: A total of 400 cases were reported, with 277 (69%) fetuses (185 ≤24 weeks' gestation and 92 >24 weeks' gestation) and 123 children (42 newborns aged <1 month, 53 infants ≤12 months and 28 children ≤16 years). Musculoskeletal (MSK) abnormalities were found at autopsy in 47/400 (11.7%). Overall sensitivity and specificity (with 95% confidence interval) of PMMR for MSK pathology were 51.1% (37.0, 65.0) and 98.2% (96.2, 99.2), with positive and negative predictive values of 79.3% (61.6, 90.2) and 93.8% (90.8, 95.9), respectively. Overall accuracy between PMMR and autopsy for MSK abnormalities was 92.7% (89.7, 94.9). In some cases, PMMR detected MSK abnormalities not routinely examined for or detected at traditional autopsy. CONCLUSION: Minimally invasive autopsy has good diagnostic accuracy for the exclusion of MSK abnormalities, but sensitivity is relatively poor. When PMMR is used with clinical examination and skeletal radiographs, all skeletal and soft tissue abnormalities of clinical significance are likely to be detected, even if not directly relevant to the cause of death.

Repeatability and bronchodilator reversibility of lung function in young children.

Knowledge of short- and longer-term repeatability of lung function in health and disease is essential to determine bronchodilator reversibility thresholds and to recognise if changes in lung function represent disease progression, therapeutic intervention or normal variability. Multiple-breath washout indices (lung clearance index, conductive ventilation inhomogeneity (Scond)) and specific airway resistance (sRaw) were measured in healthy children and stable wheezers. Measurements were performed at baseline and after 20 min without intervention to assess repeatability and determine bronchodilator reversibility thresholds. Bronchodilator reversibility was assessed by repeating baseline measurements 20 min after inhaled salbutamol. 28 healthy controls, mean±sd age 6.1±0.7 years and 62 wheezers 5.4±0.6 years were tested. Baseline variability in multiple-breath washout indices and sRaw was not significantly different between wheezers and healthy controls. Significant bronchodilator reversibility was only observed in wheezers for Scond (16%), but in both wheezers (37%) and healthy controls (20%) for sRaw. Some wheezers and healthy controls demonstrated increases in multiple-breath washout indices post-bronchodilator. Lung clearance index and sRaw demonstrate low baseline variability in healthy and diseased subjects. Neither multiple-breath washout indices nor sRaw are ideal for assessing bronchodilator reversibility in young children with stable wheeze. These findings will help to interpret the effect of therapeutic interventions in children with respiratory diseases.

Age and height dependence of lung clearance index and functional residual capacity.

The lung clearance index (LCI) is more sensitive than spirometry in detecting abnormal lung function in children with cystic fibrosis. LCI is thought to be independent of age, but recent evidence suggests that the upper limit of normal is higher in infants and preschool children than in older subjects. This study examines whether LCI remains independent of body size throughout childhood. Multiple-breath washout data from healthy children and adolescents were collated from three centres using the mass spectrometer system and the inert gas sulfur hexafluoride. Reference equations for LCI and functional residual capacity (FRC) were constructed using the LMS (lambda-mu-sigma) method. Data were available from 497 subjects (2 weeks to 19 years of age) tested on 659 occasions. LCI was dependent on body size, decreasing in a nonlinear pattern as height increased. Changes were particularly marked in the first 5 years of life. Height, age and sex were all independent predictors of FRC. Minimal between-centre differences allowed unified reference equations to be developed. LCI is not independent of body size. Although a constant upper normal limit would suffice for cross-sectional clinical assessments from 6 years of age, appropriate reference equations are essential for accurate interpretation of results during early childhood.

A subgroup of juvenile idiopathic arthritis patients who respond well to methotrexate are identified by the serum biomarker MRP8/14 protein.

OBJECTIVES: In JIA there is an unmet need for biomarkers with which to identify patients who will respond well to MTX. The aim of this study was to define the prognostic value of baseline serum proteins and clinical variables in response to MTX to help inform the clinician at time of diagnosis whether the patient is likely to respond well to MTX. METHODS: JIA patients were recruited into the Childhood Arthritis Response to Medication Study (CHARMS). Clinical data and venous blood were collected before administration of MTX and at follow-up. MRP8/14 and inflammatory cytokines were measured by ELISA and multiplex immunoassay, respectively. CRP and ESR were measured as part of routine clinical assessment. To explore which baseline factors might predict successful treatment, binary logistic regression models were fitted for outcome. RESULTS: High disease activity (high serum MRP8/14, active joint count or physician's score) pre-MTX was observed in a subgroup of patients with a better response to therapy. In a multivariable analysis, after accounting for MRP8/14 at baseline, no other factors were independently significantly associated with outcome. Patients with baseline MRP8/14 >3000 ng/ml were more likely to respond to MTX at ACR50 or better: odds ratio 16.07 (95% CI 2.00, 129.3). CONCLUSION: We have demonstrated that high levels of baseline serum MRP8/14 have prognostic value in predicting a subgroup of patients whose arthritis will improve on MTX. Routine collection of serum prior to the start of medication would be a valuable step in collaborative validation of such biomarkers.

The analysis of record-linked data using multiple imputation with data value priors.

Probabilistic record linkage techniques assign match weights to one or more potential matches for those individual records that cannot be assigned 'unequivocal matches' across data files. Existing methods select the single record having the maximum weight provided that this weight is higher than an assigned threshold. We argue that this procedure, which ignores all information from matches with lower weights and for some individuals assigns no match, is inefficient and may also lead to biases in subsequent analysis of the linked data. We propose that a multiple imputation framework be utilised for data that belong to records that cannot be matched unequivocally. In this way, the information from all potential matches is transferred through to the analysis stage. This procedure allows for the propagation of matching uncertainty through a full modelling process that preserves the data structure. For purposes of statistical modelling, results from a simulation example suggest that a full probabilistic record linkage is unnecessary and that standard multiple imputation will provide unbiased and efficient parameter estimates.