Nonproportional hazards and unobserved heterogeneity in clustered survival data: When can we tell the difference?

Multivariate survival data are frequently encountered in biomedical applications in the form of clustered failures (or recurrent events data). A popular way of analyzing such data is by using shared frailty models, which assume that the proportional hazards assumption holds conditional on an unobserved cluster-specific random effect. Such models are often incorporated in more complicated joint models in survival analysis. If the random effect distribution has finite expectation, then the conditional proportional hazards assumption does not carry over to the marginal models. It has been shown that, for univariate data, this makes it impossible to distinguish between the presence of unobserved heterogeneity (eg, due to missing covariates) and marginal nonproportional hazards. We show that time-dependent covariate effects may falsely appear as evidence in favor of a frailty model also in the case of clustered failures or recurrent events data, when the cluster size or number of recurrent events is small. When true unobserved heterogeneity is present, the presence of nonproportional hazards leads to overestimating the frailty effect. We show that this phenomenon is somewhat mitigated as the cluster size grows. We carry out a simulation study to assess the behavior of test statistics and estimators for frailty models in such contexts. The gamma, inverse Gaussian, and positive stable shared frailty models are contrasted using a novel software implementation for estimating semiparametric shared frailty models. Two main questions are addressed in the contexts of clustered failures and recurrent events: whether covariates with a time-dependent effect may appear as indication of unobserved heterogeneity and whether the additional presence of unobserved heterogeneity can be detected in this case. Finally, the practical implications are illustrated in a real-world data analysis example.     

Is there a diurnal pattern in the clinical symptoms of HELLP syndrome?

OBJECTIVE: To determine if there is a diurnal pattern in the clinical symptoms of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) syndrome. STUDY DESIGN: A retrospective study was performed in 134 pregnancies complicated by HELLP syndrome. The medical records were reviewed to describe each HELLP episode. Time of day was divided into three periods, day, evening, and night. The following parameters were categorized according to the time of day: onset of symptoms, consultation by the doctor, initial blood sampling, diagnosis and decrease of symptoms. Biochemical parameters at clinical presentation and consecutive changes within 24 h were recorded. RESULTS: In 65 pregnancies 77 HELLP episodes were well documented. Times of onset of symptoms and consultation by the doctor were significantly higher during the evening and night (p < 0.001), whereas times of diagnosis and decrease of symptoms occurred significantly more during the day (p < 0.001). In only 49.3% of the cases were diagnostic laboratory criteria met at clinical presentation. This was mainly due to platelet values in excess of 100 x 10(9)/l. Several hours later (median 8 h, range 2-23) the decrease in platelets occurred. CONCLUSIONS: A diurnal pattern exists in the clinical symptoms of HELLP syndrome that is characterized by an exacerbation during the night and recovery during the day. There is a considerable delay between the onset of symptoms and the fulfillment of diagnostic laboratory criteria.     

Effect of maternal and infant covariates on sibship correlation in birth weight

Birth weight on 12,644 singleton infants from 6,196 sibships born in Maryland between 1980 and 1984 were used to estimate the effects of nine maternal and infant covariates on the sibship correlation in birth weight. Assuming a homogeneous correlation across all families, the estimated intraclass correlation was 0.4664 (+/- 0.0099). This high sibship correlation makes it possible to predict, with reasonable accuracy, the birth weight of a child given information on previous sibs, as well as covariates on the mother and/or infant pertinent to a given pregnancy. The reduction in variance associated with incorporating information on the nine covariates used here was approximately equal to that obtained by conditioning on a single previous sib. Testing for heterogeneity in correlation among different groups of families showed that a crude measure of parity (first live birth vs. other), time between births, mother's marital status, and maternal age at the birth of the last child significantly influenced the sibship correlation in birth weight.     

FEASIBILITY OF CONDUCTING CARDIOVASCULAR OUTCOME RESEARCH IN AUSTRALIAN GENERAL PRACTICE: RESULTS FROM THE ANBP2 PILOT STUDY

1. The present study aimed to determine the feasibility of conducting a 5 year cardiovascular outcome trial of the treatment of 6000 elderly hypertensive patients in Australian general practices. 2. General practitioners (GPs) were invited to participate by mail and personal follow-up. Patient records were reviewed to identify subjects for a blood pressure (BP) screening programme. Blood pressure was measured on three occasions and eligible subjects were included if the average BP was 160 mmHg systolic or 90 mmHg diastolic if systolic BP was 140 mmHg. 3. Seven hundred and forty-one GPs were approached and 89 were enrolled in the study (12% of mail invites and 75% of those receiving a personal contact). In 16 practices where screening was completed, 82 000 records were reviewed to identify 4% patients eligible for screening. Twenty-two per cent of eligible subjects attended screening. Of 1938 subjects screened, 180 (9%) had BP 5=160/90 mmHg. Forty-seven percent of subjects (n = 916) were receiving antihypertensive therapy and 184 (20%) were withdrawn from therapy. One hundred and sixteen (63%) of these subjects had BP return to study entry levels within 6 weeks. Fifty-seven newly diagnosed and 81 previously treated subjects were randomized (7% of the screened population). 4. Based on the high participation rate of GPs, the response rate of patients to attend a BP screening programme and the 7% randomization to screening ratio for entry into the study, the ANBP2 pilot study has demonstrated that it is feasible to recruit subjects from Australian general practices to a cardiovascular outcome trial.     

Computergestützte Charakterisierung von sonographischen Plazentastrukturen

Schlu?folgerungen Aus der Me?wert-Verteilung der Grauwerte im Sonogramm lassen sich Kennwerte berechnen, die eine computergestützte sonographische Reifebeurteilung der Plazenta erm?glichen. Allerdings sind die Verteilungsparameter (Median, Varianz, Schiefe, Exze?) abh?ngig von den Ger?teparametern. Zuverl?ssiger ist die Berechnung von Kennwerten, die sich auf die strukturellen Eigenschaften des Sonogramms beziehen. Bei den hier dargestellten Untersuchungen k?nnen Kennwerte für den Kontrast bzw. für die Ansammlung gleichartiger Grauwerte um einen bestimmten Punkt die sonographische Beurteilung der Plazenta optimieren. Damit erweitern sich die M?glichkeiten für die Zustandsdiagnostik der intrauterinen Lebensbedingungen.     

Incretin mimetics as a novel therapeutic option for hepatic steatosis.

BACKGROUND: Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is regarded as a key pathogenic factor and component of the metabolic syndrome. It was reported that administration of the incretin mimetic exenatide reversed hepatic steatosis in an obese mouse model. We had the opportunity to study the effect of additional exenatide administration on liver fat content in a patient with type 2 diabetes. CASE REPORT: A 59-year-old male with poorly controlled type 2 diabetes was treated with exenatide in addition to metformin monotherapy. Following 44 weeks of exenatide therapy, mean the liver fat measured by liver spectroscopy declined from 15.8% to 4.3%. This dramatic decrease in liver fat was accompanied by significant beneficial changes in several cardiovascular disease risk factors and improvement of all liver enzymes, in particular alanine aminotransferase, the most important marker of liver steatosis. CONCLUSION: This case report suggests that the incretin mimetic exenatide decreases hepatic fat accumulation and may play a role in the future treatment of NAFLD, and the associated insulin resistance and cardiovascular risk factors in an ever-growing high-risk population.     

A paradigm shift in treatment for atrial fibrillation: from electrical to structural therapy?

See doi:10.1016/j.ehj.2003.08.014for the article to which thiseditorial refers Atrial fibrillation (AF) is associated with increased morbidityand mortality, most notably due to stroke and heart failure.Maintaining sinus rhythm in AF patients is not an easy task,and eventually it will even fail in most leading to permanentAF. Therefore, the therapeutic goal often lies in postponingpermanent AF as long as possible. Except from the surgical correctionof mitral valve disease, almost all therapeutic approaches havebeen focused on the electrical problem that is AF. The toolsto maintain sinus rhythm, however, are suboptimal, leading tofrustration at both the side of the patient and the doctor.Anti-arrhythmic drugs prevent multiple electrical wavelets byinterfering with electrical