The R package for DICOM to brain imaging data structure conversion.

The BIDSconvertR package is the first R-based tool for organizing magnetic resonance imaging (MRI) research data in accordance with the Brain Imaging Data Structure (BIDS) specification. Key features are the DICOM (Digital Imaging and Communications in Medicine) to NIfTI (Neuroimaging Informatics Technology Initiative) and NIfTI to BIDS conversion, the implementation of the BIDS Validator and a MRI data viewer to efficiently manage MRI neuroimaging data sets. The BIDSconvertR offers an interactive user dialogue and a graphical user interface. BIDS validation is facilitated by color-coding of the BIDS sequence-IDs. Data cleaning is simplified by the option of using regular expressions. The BIDSconvertR contributes to the growing efforts to improve reproducibility in neuroimaging research by facilitating researchers to share and organize data in a standardized and transparent manner.

Real-world effectiveness of pneumococcal vaccination in older adults: Cohort study using the UK Clinical Practice Research Datalink.

BACKGROUND: The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for UK older adults, but how age moderates effectiveness is unclear. METHODS: Three annual cohorts of primary-care patients aged≥65y from the Clinical Practice Research Datalink selected from 2003-5 created a natural experiment (n = 324,804), reflecting the staged introduction of the vaccine. The outcome was symptoms consistent with community-acquired pneumococcal pneumonia (CAP) requiring antibiotics or hospitalisation. We used the prior event rate ratio (PERR) approach to address bias from unmeasured confounders. RESULTS: Vaccinated patients had higher rates of CAP in the year before vaccination than their controls, indicating the potential for confounding bias. After adjustment for confounding using the prior event rate ratio (PERR) method, PPV23 was estimated to be effective against CAP for two years after vaccination in all age sub-groups with hazard ratios (95% confidence intervals) of 0.86 (0.80 to 0.93), 0.74 (0.65 to 0.85) and 0.65 (0.57 to 0.74) in patients aged 65-74, 75-79 and 80+ respectively in the 2005 cohort. Age moderated the effect of vaccination with predicted risk reductions of 8% at 65y and 29% at 80y. CONCLUSIONS: PPV23 is moderately effective at reducing CAP among UK patients aged≥65y, in the two years after vaccination. Vaccine effectiveness is maintained, and may increase, in the oldest age groups in step with increasing susceptibility to CAP.

Effectiveness of a targeted telephone-based case management service on activity in an Emergency Department in the UK: a pragmatic difference-in-differences evaluation.

BACKGROUND: This study evaluates the effectiveness of a targeted telephone-based case management service that aimed to reduce ED attendance amongst frequent attenders, known to disproportionately contribute to demand. Evidence on the effectiveness of these services varies. METHODS: A 24-month controlled before-and-after study, following 808 patients (128 cases and 680 controls (41 were non-compliant)) who were offered the service in the first four months of operation within a UK ED department. Patients stratified as high-risk of reattending ED within 6 months by a predictive model were manually screened. Those positively reviewed were offered a non-clinical, nurse-led, telephone-based health coaching, consisting of care planning, coordination and goal setting for up to 9 months. Service effectiveness was estimated using a difference-in-differences (DiD) analysis. Incident rate of ED and Minor Injury Unit (MIU) attendances and average length of stay in intervention recipients and controls over 12 months after receiving their service offer following ED attendance were compared, adjusting for the prior 12-month period, sex and age, to give an incidence rate ratio (IRR). RESULTS: Intervention recipients were more likely to be female (63.3% versus 55.4%), younger (mean of 69 years versus 76 years), and have higher levels of ED activity (except for MIU) than controls. Mean rates fell between periods for all outcomes (except for MIU attendance). The Intention-to-Treat analysis indicated non-statistically significant effect of the intervention in reducing all outcomes, except for MIU attendances, with IRRs: ED attendances, 0.856 (95% CI: 0.631, 1.160); ED admissions, 0.871 (95% CI: 0.628, 1.208); length of stay for emergency and elective admissions: 0.844 (95% CI: 0.619, 1.151) and 0.781 (95% CI: 0.420, 1.454). MIU attendance increased with an IRR: 2.638 (95% CI: 1.041, 6.680). CONCLUSIONS: Telephone-based health coaching appears to be effective in reducing ED attendances and admissions, with shorter lengths of stay, in intervention recipients over controls. Future studies need to capture outcomes beyond acute activity, and better understand how services like this provide added value.

Influenza vaccination reduced myocardial infarctions in United Kingdom older adults: a prior event rate ratio study.

OBJECTIVES: We aimed to estimate the real-world effectiveness of the influenza vaccine against myocardial infarction (MI) and influenza in the decade since adults aged ≥ 65 years were first recommended the vaccine. STUDY DESIGN AND SETTING: We identified annual cohorts, 1997 to 2011, of adults aged ≥ 65 years, without previous influenza vaccination, from UK general practices, registered with the Clinical Practice Research Datalink. Using a quasi-experimental study design to control for confounding bias, we estimated influenza vaccine effectiveness on hospitalization for MI, influenza, and antibiotic prescriptions for lower respiratory tract infections. RESULTS: Vaccination was moderately effective against influenza, the prior event rate ratio-adjusted hazard ratios ranging from 0.70 in 1999 to 0.99 in 2001. Prior event rate ratio-adjusted hazard ratios demonstrated a protective effect against MIs, varying between 0.40 in 2010 and 0.89 in 2001. Aggregated across the cohorts, influenza vaccination reduced the risk of MIs by 39% (95% confidence interval: 34%, 44%). CONCLUSION: Effectiveness of the flu vaccine in preventing MIs in older UK adults is consistent with the limited evidence from clinical trials. Similar trends in effectiveness against influenza and against MIs suggest the risk of influenza mediates the effectiveness against MIs, although divergence in some years implies the mechanism may be complex.

Bayesian statistics in the design and analysis of cluster randomised controlled trials and their reporting quality: a methodological systematic review.

BACKGROUND: In a cluster randomised controlled trial (CRCT), randomisation units are "clusters" such as schools or GP practices. This has methodological implications for study design and statistical analysis, since clustering often leads to correlation between observations which, if not accounted for, can lead to spurious conclusions of efficacy/effectiveness. Bayesian methodology offers a flexible, intuitive framework to deal with such issues, but its use within CRCT design and analysis appears limited. This review aims to explore and quantify the use of Bayesian methodology in the design and analysis of CRCTs, and appraise the quality of reporting against CONSORT guidelines. METHODS: We sought to identify all reported/published CRCTs that incorporated Bayesian methodology and papers reporting development of new Bayesian methodology in this context, without restriction on publication date or location. We searched Medline and Embase and the Cochrane Central Register of Controlled Trials (CENTRAL). Reporting quality metrics according to the CONSORT extension for CRCTs were collected, as well as demographic data, type and nature of Bayesian methodology used, journal endorsement of CONSORT guidelines, and statistician involvement. RESULTS: Twenty-seven publications were included, six from an additional hand search. Eleven (40.7%) were reports of CRCT results: seven (25.9%) were primary results papers and four (14.8%) reported secondary results. Thirteen papers (48.1%) reported Bayesian methodological developments, the remaining three (11.1%) compared different methods. Four (57.1%) of the primary results papers described the method of sample size calculation; none clearly accounted for clustering. Six (85.7%) clearly accounted for clustering in the analysis. All results papers reported use of Bayesian methods in the analysis but none in the design or sample size calculation. CONCLUSIONS: The popularity of the CRCT design has increased rapidly in the last twenty years but this has not been mirrored by an uptake of Bayesian methodology in this context. Of studies using Bayesian methodology, there were some differences in reporting quality compared to CRCTs in general, but this study provided insufficient data to draw firm conclusions. There is an opportunity to further develop Bayesian methodology for the design and analysis of CRCTs in order to expand the accessibility, availability, and, ultimately, use of this approach.

Identification of deliberate catheter motion at the left atrial posterior wall during pulmonary vein isolation: Validity of respiratory motion adjustment.

BACKGROUND: During automated radiofrequency (RF) annotation-guided pulmonary vein isolation (PVI), respiratory motion adjustment (RMA) is recommended, yet lacks in vivo validation. METHODS: Following contact force (CF) PVI (continuous RF, 30 W) using general anesthesia and automated RF annotation-guidance (VISITAG™: force-over-time 100% minimum 1 g; 2 mm position stability; ACCURESP™ RMA "off") in 25 patients, we retrospectively examined RMA settings "on" versus "off" at the left atrial posterior wall (LAPW). RESULTS: Respiratory motion detection occurred in eight, permitting offline retrospective comparison of RMA settings. Significant differences in LAPW RF auto-annotation occurred according to RMA setting, with curves displaying catheter position, CF and impedance data indicating "best-fit" for catheter motion detection using RMA "off." Comparing RMA "on" versus "off," respectively: total annotated sites, 82 versus 98; median RF duration per-site, 13.3 versus 10.6 s (p < 0.0001); median force time integral 177 versus 130 gs (p = 0.0002); mean inter-tag distance (ITD), 6.0 versus 4.8 mm (p = 0.002). Considering LAPW annotated site 1-to-2 transitions resulting from deliberate catheter movement, 3 concurrent with inadvertent 0 g CF demonstrated < 0.6 s difference in RF duration. However, 13 deliberate catheter movements during constant tissue contact (ITD range: 2.1-7.0 mm) demonstrated (mean) site-1 RF duration difference 3.7 s (range: -1.3 to 11.3 s): considering multiple measures of catheter position instability, the appropriate indication of deliberate catheter motion occurred with RMA "off" in all. CONCLUSIONS: ACCURESP™ respiratory motion adjustment importantly delayed the identification of deliberate and clinically relevant catheter motion during LAPW RF delivery, rendering auto-annotated RF display invalid. Operators seeking greater accuracy during auto-annotated RF delivery should avoid RMA use.

Impact of influenza vaccination on amoxicillin prescriptions in older adults: A retrospective cohort study using primary care data.

BACKGROUND: Bacterial infections of the upper and lower respiratory tract are a frequent complication of influenza and contribute to the widespread use of antibiotics. Influenza vaccination may help reduce both appropriate and inappropriate prescribing of antibiotics. Electronic health records provide a rich source of information for assessing secondary effects of influenza vaccination. METHODS: We conducted a retrospective study to estimate effects of influenza vaccine on antibiotic (amoxicillin) prescription in the elderly based on data from the Clinical Practice Research Datalink. The introduction of UK policy to recommend the influenza vaccine to older adults in 2000 led to a substantial increase in uptake, creating a natural experiment. Of 259,753 eligible patients that were unvaccinated in 1999 and aged≥65y by January 2000, 88,519 patients received influenza vaccination in 2000. These were propensity score matched 1:1 to unvaccinated patients. Time-to-amoxicillin was analysed using the Prior Event Rate Ratio (PERR) Pairwise method to address bias from time-invariant measured and unmeasured confounders. A simulation study and negative control outcome were used to help strengthen the validity of results. RESULTS: Compared to unvaccinated patients, those from the vaccinated group were more likely to be prescribed amoxicillin in the year prior to vaccination: hazard ratio (HR) 1.90 (95% confidence interval 1.83, 1.98). Following vaccination, the vaccinated group were again more likely to be prescribed amoxicillin, HR 1.64 (1.58,1.71). After adjusting for prior differences between the two groups using PERR Pairwise, overall vaccine effectiveness was 0.86 (0.81, 0.92). Additional analyses suggested that provided data meet the PERR assumptions, these estimates were robust. CONCLUSIONS: Once differences between groups were taken into account, influenza vaccine had a beneficial effect, lowering the frequency of amoxicillin prescribing in the vaccinated group. Ensuring successful implementation of national programmes of vaccinating older adults against influenza may help contribute to reducing antibiotic resistance.

Transmural unipolar electrogram change occurs within 7 s at the left atrial posterior wall during pulmonary vein isolation.

BACKGROUND: To assess occurrence of a histologically validated measure of transmural (TM) atrial ablation-pure R unipolar electrogram (UE) morphology change-at first-ablated left atrial posterior wall (LAPW) sites during contact force (CF)-guided pulmonary vein isolation (PVI). METHODS: Objectively annotated VISITAG™ Module and CARTOREPLAY™ (Biosense Webster Inc., Diamond Bar, CA, USA) UE morphology data were retrospectively analyzed in 23 consecutive patients undergoing PVI under general anesthesia. RESULTS: PVI without spontaneous/dormant recovery was achieved in all, employing 16.3 (3.2) min of radiofrequency (RF; 30 W) energy. All first-ablated LAPW sites demonstrated RS UE morphology preablation, with RF-induced pure R UE morphology change in 98%. Time to pure R UE morphology was significantly shorter at left-sided LAPW sites (4.9 [2.1] vs 6.7 [2.5] s; P = .02), with significantly greater impedance drop (median 13.5 vs 9.9 Ω; P = .003). Importantly, neither first-site RF duration (14.9 vs 15.0 s) nor maximum ablation catheter tip distance moved (during RF) was significantly different, yet the mean CF was significantly higher at right-sided sites (16.5 vs 11.2 g; P = .002). Concurrent impedance and objectively annotated bipolar electrogram (BE) data demonstrated ∼6-8 Ω impedance drop and ∼30% BE decrease at the time of first pure R UE morphology change. CONCLUSIONS: Using objective ablation site annotation, UE morphology evidence of TM RF effect was demonstrated far sooner than considered biologically possible according to the "conventional" 20-40 s RF per-site approach, with significantly greater ablative effect evident at left-sided sites. This novel methodology represents a scientifically more rigorous foundation toward future research into the biological effects of RF ablation in vivo.

Adjusting for unmeasured confounding in nonrandomized longitudinal studies: a methodological review.

OBJECTIVES: Motivated by recent calls to use electronic health records for research, we reviewed the application and development of methods for addressing the bias from unmeasured confounding in longitudinal data. STUDY DESIGN AND SETTING: Methodological review of existing literature. We searched MEDLINE and EMBASE for articles addressing the threat to causal inference from unmeasured confounding in nonrandomized longitudinal health data through quasi-experimental analysis. RESULTS: Among the 121 studies included for review, 84 used instrumental variable analysis (IVA), of which 36 used lagged or historical instruments. Difference-in-differences (DiD) and fixed effects (FE) models were found in 29 studies. Five of these combined IVA with DiD or FE to try to mitigate for time-dependent confounding. Other less frequently used methods included prior event rate ratio adjustment, regression discontinuity nested within pre-post studies, propensity score calibration, perturbation analysis, and negative control outcomes. CONCLUSION: Well-established econometric methods such as DiD and IVA are commonly used to address unmeasured confounding in nonrandomized longitudinal studies, but researchers often fail to take full advantage of available longitudinal information. A range of promising new methods have been developed, but further studies are needed to understand their relative performance in different contexts before they can be recommended for widespread use.

Anti-Müllerian hormone in children: a ten-year prospective longitudinal study (EarlyBird 39).

BACKGROUND: Anti-Müllerian hormone (AMH) is produced by Sertoli cells of the testes and granulosa cells of the ovary. There are limited prospective longitudinal data assessing AMH concentrations throughout childhood in both sexes. OBJECTIVE: This study aimed to examine AMH throughout childhood with particular reference to the relationship of AMH to pubertal development in both sexes. DESIGN: This is a prospective longitudinal non-intervention cohort study with annual sampling for participants aged 5-14 years. SETTING: Community cohort study. PARTICIPANTS: A total of 307 healthy children (170 boys) recruited at 5 years from randomly selected schools in Plymouth, UK, participated in this study. Data sets are complete in 76% of the children at 14 years of age. MAIN OUTCOME MEASURE(S): Annual measures of serum AMH, follicle stimulating hormone (FSH) and luteinising hormone (LH), Tanner stage (TS). RESULTS: Boys: AMH was stable from 5 to 7 years, increased slightly from 8 to 10 years, then declined at TS2. This decline was preceded by rising FSH and the appearance of LH. AMH correlated inversely with gonadotrophic hormones during puberty. Girls: AMH increased slightly between 6 and 10 years, peaking during the final prepubertal year before returning to near baseline levels at TS3. Inverse correlations between AMH and FSH were apparent during the prepubertal years. CONCLUSIONS: Our longitudinal data clarified the development of individual AMH levels over a 10-year period. We described modest late prepubertal peaks in both boys and girls, and confirmed the pubertal decline in boys. The inverse association of AMH with gonadotrophins in young females supports its role as a marker of ovarian function, while the precise role for AMH in relation to testicular function in young males remains unclear.

Divergence between HbA1c and fasting glucose through childhood: implications for diagnosis of impaired fasting glucose (Early Bird 52).

OBJECTIVE: An HbA1c threshold of ≥ 6.5% has recently been adopted for the diagnosis of diabetes in adults, and of ≥ 5.7% to identify adults at risk. Little,however, is known of HbA1c's behaviour or diagnostic value in youth. Our aim was to describe the course of HbA1c during childhood, and its association with fasting glucose. RESEARCH DESIGN AND METHODS: HbA1c and glucose were measured every year in a cohort of 326 healthy children (162 boys) from 5 to 15 years. Mixed effects modelling was used to establish the determinants of HbA1c and its development over time. ROC analysis was used to determine the diagnostic value of HbA1c in the 55 individuals who showed impaired fasting glucose(IFG ­ glucose ≥ 5.6 mmol/L). RESULTS: Glucose rose progressively from 4.3 mmol/L at 5 years to 5.1 mmol/Lat 15 years, and although there were positive associations between HbA1c and glucose, from 10 to 13 years, HbA1c fell while glucose continued to rise. IFG developed in 55 children, but HbA1c exceeded 5.7% in only 16 of them. The maximum area under the ROC curve was 0.71 at the age of 14 (p<0.001), and the sensitivity and specificity were optimal at 50 and 80% respectively,corresponding to HbA1c of 5.4%. CONCLUSIONS: Although HbA1c retains a positive association with glucose throughout childhood, it is weak, and their trends diverge from 10 years,suggesting that factors other than glycaemia systematically influence the variance of HbA1c in youth. These findings therefore limit the interpretation of HbA1c for the diagnosis of IFG during childhood.

Evidence of early beta-cell deficiency among children who show impaired fasting glucose: 10-yr cohort study (EarlyBird 56).

OBJECTIVE: Impaired fasting glucose (IFG) is a predictor of future diabetes and is increasingly common in children, but the extent to which it results from excess insulin demand or failure of supply is unclear. Our aim was to compare the behaviour of insulin sensitivity and beta-cell function in children who developed IFG with those whose glucose levels remained within the normal range. METHODS: We examined trends in fasting glucose, insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B) in 327 healthy children annually from 5 to 15 yr, and the parents at baseline. RESULTS: Fifty-five children showed IFG, mostly after age 11 yr. Fasting glucose rose progressively and was higher throughout in those who developed IFG compared with those who did not (p < 0.001). Beta-cell function was lower from the age of 5 yr in those who developed IFG (p = 0.006), but there was no difference in BMI (p = 0.71). A difference in insulin sensitivity was revealed on adjustment for covariates (p = 0.03). Glucose was higher (p < 0.001), beta-cell function lower (p = 0.01), and insulin sensitivity the same (p = 0.86) in the mothers of children who showed IFG, compared with those who did not. CONCLUSIONS: IFG is common in contemporary children, and appears to be related to a defect in beta-cell function already present at 5 yr. Similar findings in the mothers of IFG children suggest that the beta-cell defect may be transmissible.

Age before stage: insulin resistance rises before the onset of puberty: a 9-year longitudinal study (EarlyBird 26).

OBJECTIVE: Insulin resistance (IR) is associated with diabetes. IR is higher during puberty in both sexes, with some studies showing the increase to be independent of changes in adiposity. Few longitudinal studies have reported on children, and it remains unclear when the rise in IR that is often attributed to puberty really begins. We sought to establish from longitudinal data its relationship to pubertal onset, and interactions with age, sex, adiposity, and IGF-1. RESEARCH DESIGN AND METHODS: The EarlyBird Diabetes study is a longitudinal prospective cohort study of healthy children aged 5-14 years. Homeostasis model assessment (HOMA-IR), skinfolds (SSF), adiposity (percent fat, measured by dual-energy X-ray absorptiometry), serum leptin, and IGF-1 were measured annually in 235 children (134 boys). Pubertal onset was adduced from Tanner stage (TS) and from the age at which luteinizing hormone (LH) first became serially detectable (≥0.2 international units/L). RESULTS: IR rose progressively from age 7 years, 3-4 years before TS2 was reached or LH became detectable. Rising adiposity and IGF-1 together explained 34% of the variance in IR in boys and 35% in girls (both P < 0.001) over the 3 years preceding pubertal onset. The contribution of IGF-1 to IR was greater in boys, despite their comparatively lower IGF-1 levels. CONCLUSIONS: IR starts to rise in mid-childhood, some years before puberty. Its emergence relates more to the age of the child than to pubertal onset. More than 60% of the variation in IR prior to puberty was unexplained. The demography of childhood diabetes is changing, and prepubertal IR may be important.