On estimating treatment effects under non‐compliance in randomized clinical trials: are intent‐to‐treat or instrumental variables analyses perfect solutions?

In this report, we compared four estimators (intent-to-treat, as treated, per protocol, and instrumental variables estimators) that are conventionally considered for treatment effect estimation by simulation under different non-compliance scenarios in typical clinical trial settings. We found that intent-to-treat and instrumental variables estimators are not perfect and can be problematic in some situations although these two estimators carry desirable properties as we assume.     

Prognostic variables in newly diagnosed childhood immune thrombocytopenia

Immune thrombocytopenia (ITP) has a favorable prognosis in children. Only a small number of children go on to develop chronic ITP. However, at the time of diagnosis, it is not possible to predict the course of the disease. In order to determine prognostic factors that could predict the disease course at diagnosis, we retrospectively evaluated various clinical variables in 103 pediatric patients with newly diagnosed ITP at our institution from 1995 to 2001. Sixty-eight (66%) patients had a mean platelet volume (MPV) of <8 fL on admission. Of 72 patients who had a follow-up period of at least 6 months, 54 (75%) achieved a durable remission within 6 months and 18 (25%) developed chronic ITP. In univariate analysis, a low admission MPV (<8), history of viral prodrome, and a low admission platelet count (<10 x 10(9)/L) predicted for a favorable outcome. Age and sex did not correlate with remission. In multivariate analysis, a low admission MPV and a history of a viral prodrome were the only independent factors correlated with a durable CR. The adjusted odds ratio for achieving a durable remission was 8.9 (95% CI: 1.54-51.8) for history of a viral prodrome and 14 (95% CI: 2.52-83.3) for low admission MPV value. In conclusion, our study showed that a majority of the children with newly diagnosed ITP presented with a low MPV value. A history of viral illness and a low admission MPV were found to be independent prognostic variables that predicted for the achievement of a durable CR in childhood ITP.     

Autonomic and EEG correlates of emotional imagery in subjects with different hypnotic susceptibility

The autonomic and EEG correlates of the response to a cognitive unpleasant stimulation (US) verbally administered to awake hypnotizable and non hypnotizable subjects were studied. They were compared with the values obtained during a resting condition immediately preceding the stimulus and with those produced by a cognitive neutral stimulation (NS), also administered after a basal resting period. Results showed hypnotic trait effects on skin resistance, heart and respiratory rate as well as on EEG theta, alpha, beta and gamma relative power changes. The autonomic and EEG patterns observed indicated different strategies in the task execution for hypnotizable and non hypnotizable subjects and a discrepancy between the autonomic and EEG changes associated to the US in susceptible subjects. Results support dissociation theories of hypnosis and suggest for hypnotizable persons an active mechanism of protection against cardiac hazard.     

Normative vibrotactile thresholds measured at five European test centres

Objectives To compare vibrotactile thresholds between five international test centres, to determine causes of variability, and to provide normative data for use by health professionals.Methods Vibrotactile thresholds were measured on various fingers in 1,008 subjects at 31.5 Hz (2,531 measurements) and at 125 Hz (2,807 measurements). Three centres used the up-and-down method of limits, rate of change of stimulus 3dB/s, to obtain vibrotactile thresholds. The push force on the surround was 2 N, the probe contact force was 1 N and the probe diameter was 6 mm concentric to a 10-mm diameter hole in the surround. One centre used an up-and-down method of limits with a 5-dB step and a 1.26-mm diameter probe with no surround. Another centre used a stepping algorithm, no surround, and the force on the 6-mm-diameter probe was unspecified.Results The 31.5-Hz thresholds and 125-Hz thresholds, expressed in dB, were similar between centres using similar methods. There were small (<5 dB) differences in vibrotactile thresholds between male and female subjects, between white-collar and blue-collar workers and between fingers. Both 31.5-Hz and 125-Hz thresholds increased with age; the mean effect of age on 31.5-Hz thresholds was approximately 2 dB over 25 years, while the effect of age on 125 Hz-thresholds was as high as 10 dB over 25 years.Conclusions Vibrotactile thresholds are influenced by measurement method but can be similar at different centres if similar methods are used. Effects of measurement location and gender are often negligible. Thresholds depend on age, but over the range of ages considered, only the effect on 125-Hz thresholds is sufficient for correction; methods of correcting for age are given. These normative data may be used to assist the diagnosis of peripheral neuropathy involving vibrotactile sensation.     

Consequences of exposure measurement error for confounder identification in environmental epidemiology

Non-differential measurement error in the exposure variable is known to attenuate the dose-response relationship. The amount of attenuation introduced in a given situation is not only a function of the precision of the exposure measurement but also depends on the conditional variance of the true exposure given the other independent variables. In addition, confounder effects may also be affected by the exposure measurement error. These difficulties in statistical model development are illustrated by examples from a epidemiological study performed in the Faroe Islands to investigate the adverse health effects of prenatal mercury exposure.     

Clinical variables associated with the isolation of Klebsiella pneumoniae expressing different extended-spectrum β-lactamases

Clinical variables associated with the isolation of Klebsiella pneumoniae expressing different extended-spectrum beta-lactamases (ESBLs) were studied. Clinical records of patients with ESBL-positive K. pneumoniae isolates between 1989 and 2003 (n = 80) were reviewed retrospectively. Patients with SHV- and TEM-type ESBLs were identified more frequently in the intensive care units (67% and 78%, respectively), whereas those with CTX-M ESBLs were found in medical wards (52.2%) or were outpatients (17.4%) (p <0.01). The absence of urinary or central catheters was associated with CTX-M-10 (p 0.013 and p <0.01, respectively). Central catheter-related infections and secondary bacteraemia were associated more frequently with SHV- and TEM-type ESBLs, whereas urinary tract infections were associated with CTX-M-10. Previous aminoglycoside use was associated particularly with SHV-type ESBLs (p <0.01), whereas amoxycillin-clavulanate and oral cephalosporins were associated with CTX-M-10 (p <0.01 and p 0.050, respectively). The frequency of adequate empirical treatment was low (22%), and 61% of patients were treated according to the susceptibility testing results. Mortality (22%) and related mortality (14%) did not differ statistically according to the type of ESBL. Different ESBL types in K. pneumoniae were associated with different clinical variables, and this should be taken into account in current and future epidemiological scenarios.     

中国式DRGs的控费机理及其控费效果的环境变量分析

DRGs是世界公认的比较先进的支付方式之一,它能在一定程度上控制医疗费用的不合理增长。我国也开始探讨DRGs支付方式,试图在医保控费中发挥积极作用。与国外DRGs相比,中国式DRGs具有独特的控费机理,其控费效果如何会受到许多环境变量的影响。     

On Enrichment Strategies for Biomarker Stratified Clinical Trials

ABSTRACT

In the era of precision medicine, drugs are increasingly developed to target subgroups of patients with certain biomarkers. In large all-comer trials using a biomarker stratified design, the cost of treating and following patients for clinical outcomes may be prohibitive. With a fixed number of randomized patients, the efficiency of testing certain treatments parameters, including the treatment effect among biomarker-positive patients and the interaction between treatment and biomarker, can be improved by increasing the proportion of biomarker positives on study, especially when the prevalence rate of biomarker positives is low in the underlying patient population. When the cost of assessing the true biomarker is prohibitive, one can further improve the study efficiency by oversampling biomarker positives with a cheaper auxiliary variable or a surrogate biomarker that correlates with the true biomarker. To improve efficiency and reduce cost, we can adopt an enrichment strategy for both scenarios by concentrating on testing and treating patient subgroups that contain more information about specific treatment parameters of primary interest to the investigators. In the first scenario, an enriched biomarker stratified design enriches the cohort of randomized patients by directly oversampling the relevant patients with the true biomarker, while in the second scenario, an auxiliary-variable-enriched biomarker stratified design enriches the randomized cohort based on an inexpensive auxiliary variable, thereby avoiding testing the true biomarker on all screened patients and reducing treatment waiting time. For both designs, we discuss how to choose the optimal enrichment proportion when testing a single hypothesis or two hypotheses simultaneously. At a requisite power, we compare the two new designs with the BSD design in terms of the number of randomized patients and the cost of trial under scenarios mimicking real biomarker stratified trials. The new designs are illustrated with hypothetical examples for designing biomarker-driven cancer trials.