Overstating the evidence - double counting in meta-analysis and related problems

Background: The problem of missing studies in meta-analysis has received much attention. Less attention has been paid to the more serious problem of double counting of evidence. Methods: Various problems in overstating the precision of results from meta-analyses are described and illustrated with examples, including papers from leading medical journals. These problems include, but are not limited to, simple double-counting of the same studies, double counting of some aspects of the studies, inappropriate imputation of results, and assigning spurious precision to individual studies. Results: Some suggestions are made as to how the quality and reliability of meta-analysis can be improved. It is proposed that the key to quality in meta-analysis lies in the results being transparent and checkable. Conclusions: Existing quality check lists for meta-analysis do little to encourage an appropriate attitude to combining evidence and to statistical analysis. Journals and other relevant organisations should encourage authors to make data available and make methods explicit. They should also act promptly to withdraw meta-analyses when mistakes are found

Harold Jeffreys's Theory of Probability Revisited

Published exactly seventy years ago, Jeffreys's Theory of Probability (1939) has had a unique impact on the Bayesian community and is now considered to be one of the main classics in Bayesian Statistics as well as the initiator of the objective Bayes school. In particular, its advances on the derivation of noninformative priors as well as on the scaling of Bayes factors have had a lasting impact on the field. However, the book reflects the characteristics of the time, especially in terms of mathematical rigor. In this paper we point out the fundamental aspects of this reference work, especially the thorough coverage of testing problems and the construction of both estimation and testing noninformative priors based on functional divergences. Our major aim here is to help modern readers in navigating in this difficult text and in concentrating on passages that are still relevant today.Comment: This paper commented in: [arXiv:1001.2967], [arXiv:1001.2968], [arXiv:1001.2970], [arXiv:1001.2975], [arXiv:1001.2985], [arXiv:1001.3073]. Rejoinder in [arXiv:0909.1008]. Published in at http://dx.doi.org/10.1214/09-STS284 the Statistical Science (http://www.imstat.org/sts/) by the Institute of Mathematical Statistics (http://www.imstat.org

Tibial or hip BMD predict clinical fracture risk equally well: results from a prospective study in 700 elderly Swiss women

Summary: In a randomly selected cohort of Swiss community-dwelling elderly women prospectively followed up for 2.8 ± 0.6years, clinical fractures were assessed twice yearly. Bone mineral density (BMD) measured at tibial diaphysis (T-DIA) and tibial epiphysis (T-EPI) using dual-energy X-ray absorptiometry (DXA) was shown to be a valid alternative to lumbar spine or hip BMD in predicting fractures. Introduction: A study was carried out to determine whether BMD measurement at the distal tibia sites of T-EPI and T-DIA is predictive of clinical fracture risk. Methods: In a predefined representative cohort of Swiss community-dwelling elderly women aged 70-80years included in the prospective, multi-centre Swiss Evaluation of the Methods of Measurement of Osteoporotic Fracture risk (SEMOF) study, fracture risk profile was assessed and BMD measured at the lumbar spine (LS), hip (HIP) and tibia (T-DIA and T-EPI) using DXA. Thereafter, clinical fractures were reported in a bi-yearly questionnaire. Results: During 1,786 women-years of follow-up, 68 clinical fragility fractures occurred in 61 women. Older age and previous fracture were identified as risk factors for the present fractures. A decrease of 1 standard deviation in BMD values yielded a 1.5-fold (HIP) to 1.8-fold (T-EPI) significant increase in clinical fragility fracture hazard ratio (adjusted for age and previous fracture). All measured sites had comparable performance for fracture prediction (area under the curve range from 0.63 [LS] to 0.68 [T-EPI]). Conclusion: Fracture risk prediction with BMD measurements at T-DIA and T-EPI is a valid alternative to BMD measurements at LS or HIP for patients in whom these sites cannot be accessed for clinical, technical or practical reason

Fracture hospitalizations between years 2000 and 2007 in Switzerland: a trend analysis

Summary: In Switzerland, the total number and incidence of hospitalizations for major osteoporotic fractures increased between years 2000 and 2007, while hospitalizations due to hip fracture decreased. The cost impact of shorter hospital stays was offset by the increasing cost per day of hospitalization. Introduction: The aim of the study was to establish the trends and epidemiological characteristics of hospitalizations for major osteoporotic fractures (MOF) between years 2000 and 2007 in Switzerland. Methods: Sex- and age-specific trends in the number and crude and age-standardized incidences of hospitalized MOF (hip, clinical spine, distal radius, and proximal humerus) in women and men aged ≥45years were analyzed, together with the number of hospital days and cost of hospitalization, based on data from the Swiss Federal Statistical Office hospital database and population statistics. Results: Between 2000 and 2007, the absolute number of hospitalizations for MOF increased by 15.9% in women and 20.0% in men, mainly due to an increased number of non-hip fractures (+37.7% in women and +39.7% in men). Hospitalizations for hip fractures were comparatively stable (−1.8% in women and +3.3% in men). In a rapidly aging population, in which the number of individuals aged ≥45years grew by 11.1% (women) and 14.6% (men) over the study period, the crude and age-standardized incidences of hospitalizations decreased for hip fractures and increased for non-hip MOF, both in women and men. The length of hospital stay decreased for all MOF in women and men, the cost impact of which was offset by an increase in the daily costs of hospitalization. Conclusions: Between years 2000 and 2007, hospitalizations for MOF continued to increase in Switzerland, driven by an increasing number and incidence of hospitalizations for non-hip fractures, although the incidence of hip fractures has decline

Comparative trends in hospitalizations for osteoporotic fractures and other frequent diseases between 2000 and 2008

Summary: In Switzerland, the number, incidence, and cost of acute hospitalizations for major osteoporotic fractures (MOF) and major cardiovascular events (MCE) increased in both women and men between 2000 and 2008, although the mean length of stay (LOS) was significantly reduced. Similar trend patterns were observed for hip fractures and strokes (decrease) and nonhip fractures and acute myocardial infarctions (increase). Introduction: The purpose of this study was to compare the trends and epidemiological characteristics of hospitalizations for MOF and other frequent diseases between years2000 and 2008 in Switzerland. Methods: Trends in the number, age-standardized incidence, mean LOS, and cost of hospitalized MOF and MCE (acute myocardial infarction, stroke, and heart failure) were compared in women and men aged ≥45years, based on data from the Swiss Federal Statistical Office. Results: Between 2000 and 2008, the incidence of acute hospitalizations for MOF increased by 3.4% in women and 0.3% in men. In both sexes, a significant decrease in hip fractures (−15.0% and −11.0%) was compensated by a concomitant, significant increase in nonhip fractures (+24.8% and +13.8%). Similarly, the incidence of acute hospitalizations for MCE increased by 4.4% in women and 8.2% in men, as an aggregated result from significantly increasing acute myocardial infarctions and significantly decreasing strokes. While the mean LOS in the acute inpatient setting decreased almost linearly between years2000 and 2008 in all indications, the inpatient costs increased significantly (p < 0.001) for MOF (+30.1% and +42.7%) and MCE (+22.6% and +47.1%) in women and men, respectively. Conclusions: Between years2000 and 2008, the burden of hospitalized osteoporotic fractures to the Swiss healthcare system has continued to increase in both sexes. In women, this burden was significantly higher than that of MCE and the gap widened over tim

Response of Spiking Neurons to Correlated Inputs

The effect of a temporally correlated afferent current on the firing rate of a leaky integrate-and-fire (LIF) neuron is studied. This current is characterized in terms of rates, auto and cross-correlations, and correlation time scale $\tau_c$ of excitatory and inhibitory inputs. The output rate $\nu_{out}$ is calculated in the Fokker-Planck (FP) formalism in the limit of both small and large $\tau_c$ compared to the membrane time constant $\tau$ of the neuron. By simulations we check the analytical results, provide an interpolation valid for all $\tau_c$ and study the neuron's response to rapid changes in the correlation magnitude.Comment: 4 pages, 3 figure

Understanding Variation in Sets of N-of-1 Trials.

A recent paper in this journal by Chen and Chen has used computer simulations to examine a number of approaches to analysing sets of n-of-1 trials. We have examined such designs using a more theoretical approach based on considering the purpose of analysis and the structure as regards randomisation that the design uses. We show that different purposes require different analyses and that these in turn may produce quite different results. Our approach to incorporating the randomisation employed when the purpose is to test a null hypothesis of strict equality of the treatment makes use of Nelder's theory of general balance. However, where the purpose is to make inferences about the effects for individual patients, we show that a mixed model is needed. There are strong parallels to the difference between fixed and random effects meta-analyses and these are discussed

Initial prognostic factors in small-cell lung cancer patients predicting quality of life during chemotherapy. Swiss Group for Clinical Cancer Research (SAKK).

The question of whether initial prognostic factors in small-cell lung cancer patients have a predictive value for patients' quality of life (QL) during chemotherapy is addressed in the context of a randomised clinical trial comparing early and late alternating chemotherapy (SAKK protocol 15/84). The relative impact of initial tumour stage and performance status, previous weight loss, sex and age on patient-rated QL was analysed over six chemotherapy cycles in 124-130 patients (according to available QL data) with more than 400 questionnaires. Fatigue/malaise, personal functioning, emotional and general well-being were prospectively selected as QL indicators. Predefined summary measures (average QL score over chemotherapy cycles, 'minimum', 'maximum' and 'final' improvement) were analysed separately by scale in various patient groups. General linear models adjusted for treatment arm and response were used to confirm the univariate findings. Within the overall sample, the average QL scores over six cycles were predicted by initial prognostic factors. Patients with poor prognostic factors reported worse QL. Within a limited sample (with baseline QL), patients with poor prognostic factors reported worse QL at baseline and greater improvement under treatment. Graphical comparison of QL patterns over cycles showed permanent discrimination by levels of prognostic factors. The impact of initial prognostic factors was consistently confirmed in the three analyses. Levels of performance status and weight loss best discriminated QL. Initial tumour stage, performance status and previous weight loss can predict QL in small-cell lung cancer during chemotherapy, even after controlling for response to treatment. Our results may contribute to clinical decision-making with regard to the intensity of chemotherapy and QL outcome, especially in patients with extensive disease

Low Momentum Scattering in the Dirac Equation

It is shown that the amplitude for reflection of a Dirac particle with arbitrarily low momentum incident on a potential of finite range is -1 and hence the transmission coefficient T=0 in general. If however the potential supports a half-bound state at k=0 this result does not hold. In the case of an asymmetric potential the transmission coefficient T will be non-zero whilst for a symmetric potential T=1.Comment: 12 pages; revised to include additional references; to be published in J Phys