Using Bayesian Dynamic Borrowing to Maximize the Use of Existing Data: A Case-Study.

Bayesian Dynamic Borrowing (BDB) designs are being increasingly used in clinical drug development. These methods offer a mathematically rigorous and robust approach to increase efficiency and strengthen evidence by integrating existing trial data into a new clinical trial. The regulatory acceptability of BDB is evolving and varies between and within regulatory agencies. This paper describes how BDB can be used to design a new randomised clinical trial including external data to supplement the planned sample size and discusses key considerations related to data re-use and BDB in drug development programs. A case-study illustrating the planning and evaluation of a BDB approach to support registration of a new medicine with the Center for Drug Evaluation in China will be presented. Key steps and considerations for the use of BDB will be discussed and evaluated, including how to decide whether it is appropriate to borrow external data, which external data can be re-used, the weight to put on the external data and how to decide if the new study has successfully demonstrated treatment benefit.

[The Jena standing stability (JESS) score : Development, standard value generation and clinical applicability of a score for evaluation of standing stability]. / Der Jenaer-Stand-Stabilitäts-Score (JESS-Score) : Entwicklung, Normwertgenerierung und klinische Anwendbarkeit eines Scores zur Evaluation der Standstabilität.

BACKGROUND: Standing can be understood as a motor process in addition to the stereotypes of movement described by Janda. Atypical stress during standing leads to overstraining of myofascial structures and to pain. The search for a specific examination possibility with the prospect of individual therapy recommendations was the reason for the development of this score. METHODOLOGY: In this study 80 healthy volunteers were examined for their stance stability by means of established as well as proportionally newly described test procedures. The equally weighted results were combined into a score and its standard values were determined. RESULTS: For the age group 18-44 years old the norm is the completion of 10 out of the total of 13 individual tasks. For the age group 45-59 years old, according to current measurements 8 out of 13 achieved points are the norm. In the age group from the age of 60 years onwards, no reliable statements can so far be made. DISCUSSION: The age group up to 44 years old provided reliable data. The age group above that shows at least a clear trend. The existing tests and scores are increasingly concerned with the risk of falling and the dexterity in movements and complex tasks. The status as a motor stereotype has not yet been described. After an examination using the Jena standing stability (JESS) score it is possible to make statements about individual therapy priorities. CONCLUSION: The JESS score is a practicable test to verify the standing stereotype. The extension of the norm group by including further study participants will decide on a stabilization or modification of the current results. The testing of further cohorts will show to what extent these items are sensitive to changes caused by training methods and whether the score can also be used to congruently map clinical changes.

Bile acids drive the newborn's gut microbiota maturation.

Following birth, the neonatal intestine is exposed to maternal and environmental bacteria that successively form a dense and highly dynamic intestinal microbiota. Whereas the effect of exogenous factors has been extensively investigated, endogenous, host-mediated mechanisms have remained largely unexplored. Concomitantly with microbial colonization, the liver undergoes functional transition from a hematopoietic organ to a central organ of metabolic regulation and immune surveillance. The aim of the present study was to analyze the influence of the developing hepatic function and liver metabolism on the early intestinal microbiota. Here, we report on the characterization of the colonization dynamics and liver metabolism in the murine gastrointestinal tract (n = 6-10 per age group) using metabolomic and microbial profiling in combination with multivariate analysis. We observed major age-dependent microbial and metabolic changes and identified bile acids as potent drivers of the early intestinal microbiota maturation. Consistently, oral administration of tauro-cholic acid or ß-tauro-murocholic acid to newborn mice (n = 7-14 per group) accelerated postnatal microbiota maturation.

[Clinical application of the Bregma test : Point prevalence in healthy, pain-free and chronic pain patients and change of test results during interdisciplinary multimodal pain therapy]. / Klinische Anwendung des Bregmatests : Punktprävalenz an Gesunden, Nichtschmerzpatienten und chronischen Schmerzpatienten sowie Änderung der Testergebnisse während einer interdisziplinären multimodalen Schmerztherapie.

BACKGROUND: The Bregma test as an investigation of sensorimotor deficits has not yet been broadly applied. It is considered to be a test for the presentation of general sensorimotor abilities in a standing position. Pain patients often show disorders in physical perception and movement. OBJECTIVE: Are there differences in the point prevalence of the Bregma test in patients (with and without diagnosis F45.41) or healthy persons? In a second part the development of pathological Bregma test values was observed in the context of an interdisciplinary multimodal pain therapy (IMST). MATERIAL AND METHODS: Point prevalence of pathological test results in 3 groups, total n = 218. Monitoring of the course of an IMST at the beginning and end of a day clinic setting, n = 60. RESULTS: Healthy and "non-F45.41" patients showed a <15% frequency of pathological Bregma test results. In "F45.41 patients" the frequency was >50%. Within the framework of an IMST the pathological movements could be reduced to approximately 33%. CONCLUSION: Increased body perception disorders are known in chronic pain patients. The Bregma test is able to detect at least some of the patients with sensorimotor deficits. Chronic pain patients significantly differ from healthy or other patient groups. The deficits in the controllability of myofascial tissue (coordination) can also be improved during a 4-week IMST.

Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Uncovering selection bias in case-control studies using Bayesian post-stratification.

Case-control studies are particularly prone to selection bias, which can affect odds ratio estimation. Approaches to discovering and adjusting for selection bias have been proposed in the literature using graphical and heuristic tools as well as more complex statistical methods. The approach we propose is based on a survey-weighting method termed Bayesian post-stratification and follows from the conditional independences that characterise selection bias. We use our approach to perform a selection bias sensitivity analysis by using ancillary data sources that describe the target case-control population to re-weight the odds ratio estimates obtained from the study. The method is applied to two case-control studies, the first investigating the association between exposure to electromagnetic fields and acute lymphoblastic leukaemia in children and the second investigating the association between maternal occupational exposure to hairspray and a congenital anomaly in male babies called hypospadias. In both case-control studies, our method showed that the odds ratios were only moderately sensitive to selection bias.

[Plantar fasciitis due to driving lessons?]. / Fasziitis plantaris durch PKW-Fahrschule?

A first league female soccer player presented with the symptoms of a fasciitis plantaris of the left foot. After treatment and a training pause she complained about the same symptoms in the other foot. In our opinion the reason for this dysfunction could be driving lessons. After interrupting the driving lessons in combination with pelvic myofascial treatment, the foot complaints were resolved. We must therefore assume that unusual actions by an athlete may lead to an overuse syndrome. The conclusion for the physicians is that it is obligatory to determine all aspects of the athletes activitis, especially those of recreation and leisure time also.

Clinical evaluation of the Oculus Keratograph.

AIM: To determine the validity and reliability of the measurement of corneal curvature and non-invasive tear break-up time (NITBUT) measures using the Oculus Keratograph. METHOD: One hundred eyes of 100 patients had their corneal curvature assessed with the Keratograph and the Nidek ARKT TonorefII. NITBUT was then measured objectively with the Keratograph with Tear Film Scan software and subjectively with the Keeler Tearscope. The Keratograph measurements of corneal curvature and NITBUT were repeated to test reliability. The ocular sensitivity disease index questionnaire was completed to quantify ocular comfort. RESULTS: The Keratograph consistently measured significantly flatter corneal curvatures than the ARKT (MSE difference: +1.83 ± 0.44D), but was repeatable (p > 0.05). Keratograph NITBUT measurements were significantly lower than observation using the Tearscope (by 12.35 ± 7.45 s; p < 0.001) and decreased on subsequent measurement (by -1.64 ± 6.03 s; p < 0.01). The Keratograph measures the first time the tears break up anywhere on the cornea with 63% of subjects having NITBUTs <5 s and a further 22% having readings between 5 and 10 s. The Tearscope results were found to correlate better with the patients symptoms (r = -0.32) compared to the Keratograph (r = -0.19). CONCLUSIONS: The Keratograph requires a calibration off-set to be comparable to other keratometry devices. Its current software detects very early tear film changes, recording significantly lower NITBUT values than conventional subjective assessment. Adjustments to instrumentation software have the potential to enhance the value of Keratograph objective measures in clinical practice.

No evidence for a correlation of glutathione S-tranferase polymorphisms and chronic rhinosinusitis.

OBJECTIVE: Cellular detoxification mechanisms are mandatory for cellular protection against oxidative stress and reactive oxygen species. One major group of antioxidative active enzymes involved in cellular detoxification are the Glutathione S-Transferases (GST). Multiple subtypes like GSTM1, GSTP1, and GSTT1 and variants of them are known, arising from allelic variations of the GST loci. Moreover, functional variants occur in high percentages and have been associated with diseases like bronchial asthma and bronchial hyperresponsiveness. The interplay of oxidative stress, detoxifying genes like GSTs and the genesis of respiratory tract illness is under contradictory debate. In this study, we analysed the potential association of GST-polymorphisms and chronic rhinosinusitis (CRS). METHODS: In total 170 nasal tissue samples, 49 tissue samples from patients with CRS without nasal polyps, 69 tissue samples from CRS with nasal polyps and 52 healthy tissue controls of the inferior turbinate were analysed for their individual GST-status. Genotypes for GSTM1 (null versus present), GSTT1 (null versus present), and GSTP1 (Ile105Val) were determined by Polymerase Chain Reaction. The respective genotypes were correlated to the incidence of CRS with and without nasal polyps in aspirin-tolerant and intolerant patients and to the individual health status concerning asthma and allergies. RESULTS: No correlation between any GST-polymorphism and CRS with and without nasal polyps or allergies or asthma or aspirin-intolerance was observed. CONCLUSION: Our results do not suggest that there is a relevant genetic predisposition considering the individual GST-status for the susceptibility of nasal respiratory epithelia leading to CRS.

Mobile phone base stations and early childhood cancers: case-control study.

OBJECTIVE: To investigate the risk of early childhood cancers associated with the mother's exposure to radiofrequency from and proximity to macrocell mobile phone base stations (masts) during pregnancy. DESIGN: Case-control study. SETTING: Cancer registry and national birth register data in Great Britain. PARTICIPANTS: 1397 cases of cancer in children aged 0-4 from national cancer registry 1999-2001 and 5588 birth controls from national birth register, individually matched by sex and date of birth (four controls per case). MAIN OUTCOME MEASURES: Incidence of cancers of the brain and central nervous system, leukaemia, and non-Hodgkin's lymphomas, and all cancers combined, adjusted for small area measures of education level, socioeconomic deprivation, population density, and population mixing. RESULTS: Mean distance of registered address at birth from a macrocell base station, based on a national database of 76,890 base station antennas in 1996-2001, was similar for cases and controls (1107 (SD 1131) m v 1073 (SD 1130) m, P=0.31), as was total power output of base stations within 700 m of the address (2.89 (SD 5.9) kW v 3.00 (SD 6.0) kW, P=0.54) and modelled power density (-30.3 (SD 21.7) dBm v -29.7 (SD 21.5) dBm, P=0.41). For modelled power density at the address at birth, compared with the lowest exposure category the adjusted odds ratios were 1.01 (95% confidence interval 0.87 to 1.18) in the intermediate and 1.02 (0.88 to 1.20) in the highest exposure category for all cancers (P=0.79 for trend), 0.97 (0.69 to 1.37) and 0.76 (0.51 to 1.12), respectively, for brain and central nervous system cancers (P=0.33 for trend), and 1.16 (0.90 to 1.48) and 1.03 (0.79 to 1.34) for leukaemia and non-Hodgkin's lymphoma (P=0.51 for trend). CONCLUSIONS: There is no association between risk of early childhood cancers and estimates of the mother's exposure to mobile phone base stations during pregnancy.

Solid fuel use and cooking practices as a major risk factor for ALRI mortality among African children.

BACKGROUND: Almost half of global child deaths due to acute lower respiratory infections (ALRIs) occur in sub-Saharan Africa, where three-quarters of the population cook with solid fuels. This study aims to quantify the impact of fuel type and cooking practices on childhood ALRI mortality in Africa, and to explore implications for public health interventions. METHODS: Early-release World Health Survey data for the year 2003 were pooled for 16 African countries. Among 32,620 children born during the last 10 years, 1455 (4.46%) were reported to have died prior to their fifth birthday. Survival analysis was used to examine the impact of different cooking-related parameters on ALRI mortality, defined as cough accompanied by rapid breathing or chest indrawing based on maternal recall of symptoms prior to death. RESULTS: Solid fuel use increases the risk of ALRI mortality with an adjusted hazard ratio of 2.35 (95% CI 1.22 to 4.52); this association grows stronger with increasing outcome specificity. Differences between households burning solid fuels on a well-ventilated stove and households relying on cleaner fuels are limited. In contrast, cooking with solid fuels in the absence of a chimney or hood is associated with an adjusted hazard ratio of 2.68 (1.38 to 5.23). Outdoor cooking is less harmful than indoor cooking but, overall, stove ventilation emerges as a more significant determinant of ALRI mortality. CONCLUSIONS: This study shows substantial differences in ALRI mortality risk among African children in relation to cooking practices, and suggests that stove ventilation may be an important means of reducing indoor air pollution.

The role of biological fertility in predicting family size.

BACKGROUND: It is plausible that a couple's ability to achieve the desired number of children is limited by biological fertility, especially if childbearing is postponed. Family size has declined and semen quality may have deteriorated in much of Europe, although studies have found an increase rather than a decrease in couple fertility. METHODS: Using four high-quality European datasets, we took the reported time to pregnancy (TTP) as the predictor variable; births reported as following contraceptive failure were an additional category. The outcome variable was final or near-final family size. Potential confounders were maternal age when unprotected sex began prior to the first birth, and maternal smoking. Desired family size was available in only one of the datasets. RESULTS: Couples with a TTP of at least 12 months tended to have smaller families, with odds ratios for the risk of not having a second child approximately 1.8, and for the risk of not having a third child approximately 1.6. Below 12 months no association was observed. Findings were generally consistent across datasets. There was also a more than 2-fold risk of not achieving the desired family size if TTP was 12 months or more for the first child. CONCLUSIONS: Within the limits of the available data quality, family size appears to be predicted by biological fertility, even after adjustment for maternal age, if the woman was at least 20 years old when the couple's first attempt at conception started. The contribution of behavioural factors to this result also needs to be investigated.

Bayesian graphical models for regression on multiple data sets with different variables.

Routinely collected administrative data sets, such as national registers, aim to collect information on a limited number of variables for the whole population. In contrast, survey and cohort studies contain more detailed data from a sample of the population. This paper describes Bayesian graphical models for fitting a common regression model to a combination of data sets with different sets of covariates. The methods are applied to a study of low birth weight and air pollution in England and Wales using a combination of register, survey, and small-area aggregate data. We discuss issues such as multiple imputation of confounding variables missing in one data set, survey selection bias, and appropriate propagation of information between model components. From the register data, there appears to be an association between low birth weight and environmental exposure to NO(2), but after adjusting for confounding by ethnicity and maternal smoking by combining the register and survey data under our models, we find there is no significant association. However, NO(2) was associated with a small but significant reduction in birth weight, modeled as a continuous variable.

[Conservative therapy of cartilage defects of the upper ankle joint]. / Konservative Therapie bei Knorpelschäden am oberen Sprunggelenk.

Cartilage defects of the upper ankle joint reflect the problem that great force is transmitted and balanced out over a relatively small surface area. As a pathophysiological factor, cartilage-bone contusions play a significant role in the development of cartilage defects of the upper ankle joint. Physiotherapeutic procedures belong to the standard procedures of conservative therapy. The use and selection of the type of therapy is based on empirical considerations and experience and investigations on effectiveness of particular therapies are relatively rare. At present a symptom-oriented therapy of cartilage defects of the upper ankle joint seems to be the most sensible approach. It can be assumed that it makes sense that the symptomatic treatment of cartilage defects or initial stages of arthritis also includes the subsequent symptoms of pain, irritated condition and limited function. This leads to starting points for physiotherapy with respect to pain therapy, optimisation of pressure relationships, avoidance of pressure points, improvement of diffusion and pressure release. In addition to the differential physiotherapeutic findings, the determination of a curative, preventive or rehabilitative procedure is especially important. In physical therapy special importance is placed on a scheduled serial application corresponding to the findings, employing the necessary methods, such as physiotherapy, sport therapy, medical mechanics, manual therapy, massage, electrotherapy and warmth therapy. From this the findings-related therapy is proposed as a practical therapy concept: locomotive apparatus pain therapy, optimisation of pressure relationships, improvement of diffusion and decongestion therapy. Therapy options have been selected base on the current literature and are summarised in tabular form. The art of symptomatic therapy of cartilage defects of the upper ankle joint does not lie in the multitude of sometimes speculative procedures, but in the targeted selection of a therapy regime based on the therapeutic goal, a corresponding application dose and serial design.

Stillbirth and neonatal mortality due to congenital anomalies: temporal trends and variation by small area deprivation scores in England and Wales, 1986-96.

We investigated the variation of stillbirth and neonatal mortality due to congenital anomalies in relation to small-area measures of deprivation in a population-based study in England and Wales, 1986-96. We found 10 954 stillbirths and neonatal deaths from all non-chromosomal and chromosomal anomalies during the study period out of a total of 7 487 007 live and stillbirths. The extended perinatal mortality rate (EPM rate) (defined as babies who were stillborn or died within 28 completed days after birth per 10 000 total live and stillbirths) for all chromosomal and all non-chromosomal anomalies was 1.5/10 000 and 13.2/10 000, respectively, over the whole period. The rate for non-chromosomal anomalies halved over the decade while the rate for chromosomal anomalies remained unchanged. The relative risks of EPM for chromosomal and non-chromosomal anomalies were 0.71 [0.80, 0.95] and 1.17 [95%CI 1.06, 1.30], respectively, in the group of wards with highest deprivation compared with the least deprived group. Increasing gradients of EPM with increasing deprivation were observed for (1) grouped non-chromosomal anomalies including neural tube defects, all renal and urinary anomalies, all musculoskeletal anomalies, and multiple anomalies, and (2) several specific non-chromosomal anomalies including anencephaly, limb reduction defects, diaphragm and abdominal wall defects. This study provides strong evidence that increased deprivation is associated with increased EPM due to most non-chromosomal anomalies; the finding of decreased relative risk for chromosomal anomalies is probably related to differences in maternal age distribution between deprivation groups.

Comparison of UK paediatric cardiac surgical performance by analysis of routinely collected data 1984-96: was Bristol an outlier?

BACKGROUND: Reports of high mortality after paediatric cardiac surgery at the Bristol Royal Infirmary, UK, led to the establishment of an independent public inquiry. A key question was whether or not the mortality statistics in Bristol were unusual compared with other specialist centres. To answer this question, we did a retrospective analysis of mortality in the UK using two datasets. METHODS: Data from the UK Cardiac Surgical Register (CSR; January, 1984, to March, 1996) and Hospital Episode Statistics (HES; April, 1991, to December, 1995) were obtained for all 12 major centres in which paediatric cardiac surgery is done in the UK. The main outcome measure was mortality within 30 days of a cardiac surgical procedure. We estimated excess deaths in Bristol using a random-effects model derived from the remaining 11 centres. Additionally, a sensitivity analysis was done and case-mix examined. FINDINGS: For children younger than 1 year, in open operations, the mortality rate in Bristol was around double that of the other centres during 1991-95: within the CSR, there were 19.0 excess deaths (95% interval 2-32) among 43 deaths; and in HES, there were 24.1 excess deaths (12-34) among 41 deaths recorded. There was no strong evidence for excess mortality in Bristol for closed operations or for open operations in children older than 1 year. INTERPRETATION: Our results suggest that Bristol was an outlier, and we do not believe that statistical variation, systematic bias in data collection, case-mix, or data quality can explain a divergence in performance of this size.

Spatial variation and temporal trends of testicular cancer in Great Britain.

Increases in testicular cancer incidence have been reported in several countries over a long period. Geographical variability has also been reported in some studies. We have investigated temporal trends and spatial variation of testicular cancer at ages 20-49 in Britain. Temporal trends in testicular cancer incidence were examined, 1974 to 1991 and in mortality, 1981-1997. Spatial variation in incidence was analysed across electoral wards, 1975 to 1991. We used Poisson regression to examine for regional and socio-economic effects and Bayesian mapping techniques to analyse small-area spatial variability. Incidence increased from 6.5 to 11.1 per 100 000 in men at ages 20-34, and from 5.6 to 9.7 per 100 000 in men at ages 35-49, while mortality declined by 50% in both age groups. Risks of testicular cancer varied across regional cancer registries, ranging from 0.79 (95% CI: 0.73-0.84) to 1.32 (95% CI: 1.25-1.38), and was higher in the most affluent compared with the most deprived areas. Analyses within 2 regions (one predominantly urban, the other predominantly rural) did not indicate any localized geographical clustering. The increasing incidence contrasted with a decreasing mortality over time in Great Britain, similar to that found in other countries. The higher risk in more affluent areas is not consistent with findings on social class at the individual level. The absence of any marked geographical variability at small area scale argues against a geographically varying environmental factor operating strongly in the aetiology of testicular cancer.

Use of routinely collected data on trihalomethane in drinking water for epidemiological purposes.

OBJECTIVES: To explore the use of routinely collected trihalomethane (THM) measurements for epidemiological studies. Recently there has been interest in the relation between byproducts of disinfection of public drinking water and certain adverse reproductive outcomes, including stillbirth, congenital malformations, and low birth weight. METHOD: Five years of THM readings (1992--6), collected for compliance with statutory limits, were analysed. One water company in the north west of England, divided into 288 water zones, provided 15,984 observations for statistical analysis. On average each zone was sampled 11.1 times a year. Five year, annual, monthly, and seasonal variation in THMs were examined as well as the variability within and between zones. RESULTS: Between 1992 and 1996 the total THM (TTHM) annual zone means were less than half the statutory concentration, at approximately 46 microg/l. Differences in annual water zone means were within 7%. Over the study period, the maximum water zone mean fell from 142.2 to 88.1 microg/l. Mean annual concentrations for individual THMs (microg/l) were 36.6, 8.0, and 2.8 for chloroform, bromodichloromethane (BDCM), and dibromochloromethane (DBCM) respectively. Bromoform data were not analysed, because a high proportion of the data were below the detection limit. The correlation between chloroform and TTHM was 0.98, between BDCM and TTHM 0.62, and between DBCM and TTHM -0.09. Between zone variation was larger than within zone variation for chloroform and BDCM, but not for DBCM. There was only little seasonal variation (<3%). Monthly variation was found although there were no consistent trends within years. CONCLUSION: In an area where the TTHM concentrations were less than half the statutory limit (48 microg/l) chloroform formed a high proportion of TTHM. The results of the correlation analysis suggest that TTHM concentrations provided a good indication of chloroform concentrations, a reasonable indication of BDCM concentrations, but no indication of DBCM. Zone means were similar over the years, but the maximum concentrations reduced considerably, which suggests that successful improvements in treatment have been made to reduce high TTHM concentrations in the area. For chloroform and BDCM, the main THMs, the component between water zones was greater than variation within water zones and explained most of the overall exposure variation. Variation between months and seasons was low and showed no clear trends within years. The results indicate that routinely collected data can be used to obtain exposure estimates for epidemiological studies at a small area level.

A study of the variation in tuberculosis incidence and possible influential variables in Manchester, Liverpool, Birmingham and Cardiff in 1991-1995.

SETTING AND OBJECTIVE: The reversal of the decline in United Kingdom tuberculosis rates has sparked a resurgence of interest in the epidemiology and prevention of tuberculosis in the UK. In this paper we quantify the primary factors explaining the variability in the electoral ward level relative risk of tuberculosis in Manchester, Liverpool, Birmingham and Cardiff. DESIGN: Ecological analysis of the incidence of tuberculosis in 397 wards using hospital admissions data as a proxy for tuberculosis incidence. Admissions were evaluated from the financial years 1991/1992 to 1994/1995. Ward level covariates included measures of country of birth, ethnicity and various socio-economic measures. RESULTS: Separate analyses were carried out for pulmonary and non-pulmonary tuberculosis. For pulmonary tuberculosis the final model included measures of the ward population born in India and Pakistan, overcrowded housing and not-owner-occupied housing. For non-pulmonary tuberculosis the covariates were ward population born in India and Pakistan, overcrowded housing and the proportion of households with no car. CONCLUSIONS: The country of birth of the ward population is the single most influential explanatory factor in the variability of the ward rates for both pulmonary and non-pulmonary tuberculosis in these four cities. Measures of poverty are of secondary importance.