Helmut Schäfer

Epidemiology of invasive mycosis in ICU patients : a prospective multicenter study in 435 non-neutropenic patients

Objective: To determine the epidemiological and clinical significance of invasive fungal infections in non-neutropenic patients in intensive care who stay longer than 10 days on the intensive care unit (ICU). Design: Prospective epidemiological multicenter study over a period of 11 months, based on strict clinical, bacteriological, serological and histological criteria. Setting: Six surgical and two medical ICUs units in five university and two municipal hospitals. Patients: 435 non-neutropenic patients from medical and surgical ICUs with an ICU stay of more than 10 days. Measurements and main results: A new occurrence of invasive mycosis (3 sepsis/ 4 peritonitis/ 1 disseminated candidiasis), corresponding to the protocol conditions with onset after day 10 in the ICU, was detectable in 2.0 % (95 % confidence interval 0.85 to 3.8 %) of the 409 patients who could be assessed. Candida species were identified as an infection-relevant pathogen in all cases. The most important risk factor for the development of an invasive mycosis was the onset of peritonitis by the day 11 in the ICU (odds ratio 11.3; p = 0.003). A fungal colonization was detected in 64 % of patients (Candida species 56 %, Aspergillus 4 %, and other fungi). Six of 8 patients with an invasive mycosis died on the ICU; ICU mortality in patients with fungal colonization was 31 % and in noncolonized patients 26 %. Serological tests were not helpful clinically. The sensitivity was 88 % for the Candida HAT (haemagglutination test) (threshold titer > 1:160), 100 % for the Candida IFT (immunofluorescence test) (threshold titer > 1:80), and 50 % for the Candida Antigen Test (Candtec Ramco, threshold titer ≥ 1:8), and the specificity was 26, 6, and 73 %, respectively. The specificity for the Aspergillus HAT (threshold titer > 1:10) was 29 %. Conclusions: Invasive mycoses are rare in non-neutropenic ICU patients, even after a longer stay in the intensive care unit; fungal colonization, on the other hand, is frequently detectable. The mortality of invasive mycosis – even with systemic antimycotic therapy- was high; the mortality in patients with fungal colonization was not significantly increased compared to that in noncolonized patients. The serological test procedures, Candida HAT, Candida IFT, and the Candida Ramco Antigen Test, had a low specificity and were not helpful in diagnosing relevant invasive mycosis.

The German Multicenter, Randomized, Partially Blinded, Chronic Low-Back Pain: A Preliminary Report on the Prospective Trial of Acupuncture for Rationale and Design of the Trial

Background: The efficacy of acupuncture treatment for chronic low-back pain has not been reliably proven because of a lack of good quality studies, leading to the necessity of developing the German Acupuncture Trial for Chronic Low-Back Pain (GERAC-cLBP) study. Objective: The aim is to assess the effectiveness of traditional Chinese acupuncture for chronic low-back pain compared to sham acupuncture and with a conventional standard therapy. Methods: This trial is a nationwide, multicenter, randomized, prospective, partially blinded study. The primary endpoint is the success rate after 6 months. Success is defined as an improvement of 33% or more of three pain-related items on the Van-Korff Pain Score or an improvement of 12% or more in the disability measured by the Hanover Functional Ability Questionnaire. Assessment of the effectiveness of the blinding of patients to the form of acupuncture they received will be conducted. All clinical endpoints are assessed centrally by blinded independent observers. Th...

Exclusion of chromosomal mosaicism in prenatal diagnosis

SummaryFor use in prenatal diagnosis, tables were prepared giving the number of metaphases or clones, respectively, which must be analysed in order to detect fetal mosaicism of a given degree (=percentage of the aberrant cell population) or higher with at least 95% or 99% probability. Different tables are provided for the two techniques of chromosomal preparation: the colony method and the flask method.

Optimal multistage designs—a general framework for efficient genome-wide association studies

Genome-wide association studies (GWAS) have become increasingly affordable but they are still costly. Therefore, cost saving 2-stage designs were proposed in the literature. The restriction to 2 stages, however, seems artificial and does not exploit the full potential of the underlying methods. We extend the 2-stage approach to the general framework of any number of stages. Based on the theory of group sequential methods, we derive optimal multistage designs. With current genotyping cost structures, our results suggest that up to 4 stages are sufficient in order to get feasible and efficient designs. Furthermore, we consider the problem of choosing the optimal number of stages depending on the costs of the statistical interim analysis at each stage and provide guidelines for planning the number of stages in practice. In particular, we found that in the majority of cases both 3-stage designs and 4-stage designs are more efficient than 2-stage designs. Although prices for marker panels are showing a continuing downward trend, we still recommend implementing and using optimal multistage designs in practice. In addition to the immediate benefit, it will be necessary to acquire know-how regarding the application of multistage designs in order to be able to adapt the general framework of multistage designs to upcoming technologies in the area of GWAS.

STATISTICAL BASIS OF REFERENCE VALUES IN LABORATORY MEDICINE.

E. K. Harris and J. C. Boyd, Marcel Dekker, New York, 1995. No. of pages: 384. Price:

Diagnostic value of ambulatory Holter monitoring for the detection of coronary artery disease in patients with variable threshold angina pectoris

165. ISBN: 0-8247-9339-0

Optimal Robust Two-Stage Designs for Genome-Wide Association Studies

Patients with chronic stable angina pectoris may present with either fixed or variable threshold symptoms. To evaluate the diagnostic value of ambulatory Holter monitoring for the detection of coronary artery disease (CAD) in patients with variable threshold angina, 216 consecutive candidates for coronary angiography were investigated prospectively. For comparison, a group of 55 consecutive patients with fixed threshold angina was studied under the same conditions. Patients with prior myocardial infarction or angiographically documented CAD were excluded. Within 4 months of Holter monitoring, the advised coronary angiography was performed in 77% of the patients with variable threshold angina and in 89% of the patients with fixed threshold angina (p less than 0.05). The prevalence of CAD was markedly lower in patients with variable threshold angina compared to patients with fixed threshold angina (54 vs 90%, p less than 0.001). CAD patients of both subgroups, however, did not differ significantly with respect to the number of obstructed vessels, the Gensini coronary score, the number with impaired left ventricular function (ejection fraction less than 50%) or the duration of ischemic episodes during Holter monitoring. Diagnostic accuracy of Holter monitoring did not differ between variable and fixed threshold angina groups (67 vs 78%). In 91% of the patients results obtained by Holter monitoring could be compared to the results of a bicycle stress test. In patients with fixed threshold angina the diagnostic accuracy was similar for both tests (80 vs 80%). In patients with variable threshold angina, the diagnostic accuracy of Holter monitoring exceeded that of the exercise stress test (68 vs 55%, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Making Medical Decisions in Dependence of Genetic Background: Estimation of the Utility of DNA Testing in Clinical, Pharmaco-Epidemiological or Genetic Studies

Optimal robust two‐stage designs for genome‐wide association studies are proposed using the maximum of the recessive, additive and dominant linear trend test statistics. These designs combine cost‐saving two‐stage genotyping with robustness against misspecification of the genetic model and are much more efficient than designs based on a single model specific test statistic in detecting multiple loci with different modes of inheritance. For given power of 90%, typical cost savings of 34% can be realised by increasing the total sample size by about 13% but genotyping only about half of the sample for the full marker set in the first stage and carrying forward about 0.06% of the markers to the second stage analysis. We also present robust two‐stage designs providing optimal allocation of a limited budget for pre‐existing samples. If a sample is available which would yield a power of 90% when fully genotyped, genotyping only half of the sample due to a limited budget will typically cause a loss of power of more than 55%. Using an optimal two‐stage approach in the same sample under the same budget restrictions will limit the loss of power to less than 10%. In general, the optimal proportion of markers to be followed up in the second stage strongly depends on the cost ratio for chips and individual genotyping, while the design parameters of the optimal designs (total sample size, first stage proportion, first and second stage significance limit) do not much depend on the genetic model assumptions.

An Application of the Bootstrap in Clinical Chemistry

An index measuring the utility of testing a DNA marker before deciding between two alternative treatments is proposed which can be estimated from pharmaco‐epidemiological case‐control or cohort studies. In the case‐control design, external estimates of the prevalence of the disease and of the frequency of the genetic risk variant are required for estimating the utility index. Formulas for point and interval estimates are derived. Empirical coverage probabilities of the confidence intervals were estimated under different scenarios of disease prevalence, prevalence of drug use, and population frequency of the genetic variant. To illustrate our method, we re‐analyse pharmaco‐epidemiological case‐control data on oral contraceptive intake and venous thrombosis in carriers and non‐carriers of the factor V Leiden mutation. We also re‐analyse cross‐sectional data from the Framingham study on a gene‐diet interaction between an APOA2 polymorphism and high saturated fat intake on obesity. We conclude that the utility index may be helpful to evaluate and appraise the potential clinical and public health relevance of gene‐environment interaction effects detected in genomic and candidate gene association studies and may be a valuable decision support for designing prospective studies on the clinical utility.

Arzneimittelforschung nach der Zulassung-Ziele, Methoden und Qualitätsanforderungen-

We apply the bootstrap to a one-dimensional nonparametric discrimination problem in clinical chemistry: the construction of a cut-off point (discrimination limit) for a quantitative diagnostic test on the basis of a sample of “diseased” and “non-diseased” individuals and the subsequent evaluation of the resulting decision rule in the same sample. When the cut-off point is selected to maximize some performance criterion, the sample estimate of maximal performance is known to systematically overestimate the unknown true performance of the test at the selected cut-off point. Bootstrap methods are proposed in the classical paper by EFRON [2] to reduce bias and to obtain confidence intervals. We apply these methods and investigate their performance by a simulation study.