A distribution-free procedure for testing versatile alternative in medical multisample comparison studies.

We propose a test for multisample comparison studies that can be applied without strict assumptions, especially when the underlying population distributions are far from normal. The new test can detect differences not only in location or scale but also in shape parameters among parent population distributions. We are motivated by numerous medical studies, where the variables are not normally distributed and may present in the various groups more complex differences than simple differences in a particular aspect of underlying distributions, such as location or scale. In these situations, traditional ANOVA and Kruskal-Wallis tests are unreliable since the underlying assumptions are not valid. The proposed procedure also allows the researcher to determine which aspects are more responsible for a significant result. This is an important practical advantage over procedures that test for general differences among the distribution functions but cannot identify which aspects lead to significant results. The asymptotic distribution of the test statistic is analyzed along with its small sample behavior against several competing tests. The practical advantages of the proposed procedure are illustrated with a multisample comparison study of a biomarker for liver damage in patients with hepatitis C.

Distribution-free simultaneous tests for location-scale and Lehmann alternative in two-sample problem.

The paper deals with the classical two-sample testing problem for the equality of two populations, one of the most fundamental problems in biomedical experiments and case-control studies. The most familiar alternatives are the difference in location parameters or the difference in scale parameters or in both the parameters of the population density. All the tests designed for classical location or scale or location-scale alternatives assume that there is no change in the shape of the distribution. Some authors also consider the Lehmann-type alternative that addresses the change in shape. Two-sample tests under Lehmann alternative assume that the location and scale parameters are invariant. In real life, when a shift in the distribution occurs, one or more of the location, scale, and shape parameters may change simultaneously. We refer to change of one or more of the three parameters as a versatile alternative. Noting the dearth of literature for the equality two populations against such versatile alternative, we introduce two distribution-free tests based on the Euclidean and Mahalanobis distance. We obtain the asymptotic distributions of the two test statistics and study asymptotic power. We also discuss approximating p-values of the proposed tests in real applications with small samples. We compare the power performance of the two tests with several popular existing distribution-free tests against various fixed alternatives using Monte Carlo. We provide two illustrations based on biomedical experiments. Unlike existing tests which are suitable only in certain situations, proposed tests offer very good power in almost all types of shifts.

Pathways linking early life stress, metabolic syndrome, and the inflammatory marker fibrinogen in depressed inpatients.

BACKGROUND: Previous research has shown that metabolic syndrome as well as early life stress can account for immunoactivation (e.g. in the form of altered fibrinogen levels) in patients with major depression. This study aims at assessing the relationship between components of metabolic syndrome, early life stress and fibrinogen levels, taking the severity of depression into consideration. SUBJECTS AND METHODS: Measures of early life stress and signs of metabolic syndrome were collected in 58 adult inpatients diagnosed with depression. The relationships between the factors were assessed by means of path analyses. Two main models were tested: the first model with metabolic syndrome mediating between early life stress and fibrinogen levels and the second model without the mediating effect of metabolic syndrome. RESULTS: The first model was not supported by our data (χ²=7.02, df=1, p=0.008, CFI=0.00, NNFI=-9.44, RMSEA=0.50). The second model however provided an excellent fit for the data (χ²=0.02, df=1, p=0.90, CFI=1.00, NNFI=2.71, RMSEA=0.00). Extending the models by introducing severity of depression into them did not yield good indices of fit. CONCLUSIONS: The developmental trajectory between early life stress and inflammation appears not to be mediated by metabolic syndrome associated factors in our sample. Possible reasons including severity and type of early life stress, as well as potential epigenetic influences are discussed.

Formation of translational risk score based on correlation coefficients as an alternative to Cox regression models for predicting outcome in patients with NSCLC.

BACKGROUND: Personalised cancer therapy, such as that used for bronchial carcinoma (BC), requires treatment to be adjusted to the patient's status. Individual risk for progression is estimated from clinical and molecular-biological data using translational score systems. Additional molecular information can improve outcome prediction depending on the marker used and the applied algorithm. Two models, one based on regressions and the other on correlations, were used to investigate the effect of combining various items of prognostic information to produce a comprehensive score. This was carried out using correlation coefficients, with options concerning a more plausible selection of variables for modelling, and this is considered better than classical regression analysis. METHODS: Clinical data concerning 63 BC patients were used to investigate the expression pattern of five tumour-associated proteins. Significant impact on survival was determined using log-rank tests. Significant variables were integrated into a Cox regression model and a new variable called integrative score of individual risk (ISIR), based on Spearman's correlations, was obtained. RESULTS: High tumour stage (TNM) was predictive for poor survival, while CD68 and Gas6 protein expression correlated with a favourable outcome. Cox regression model analysis predicted outcome more accurately than using each variable in isolation, and correctly classified 84% of patients as having a clear risk status. Calculation of the integrated score for an individual risk (ISIR), considering tumour size (T), lymph node status (N), metastasis (M), Gas6 and CD68 identified 82% of patients as having a clear risk status. CONCLUSION: Combining protein expression analysis of CD68 and GAS6 with T, N and M, using Cox regression or ISIR, improves prediction. Considering the increasing number of molecular markers, subsequent studies will be required to validate translational algorithms for the prognostic potential to select variables with a high prognostic power; the use of correlations offers improved prediction.

[The effect of one year outpatient pulmonary rehabilitation on patients with COPD]. / Der Effekt von einem Jahr ambulanter pneumologischer Rehabilitation auf Patienten mit COPD.

BACKGROUND: The aim of our study was to determine the effect of one year of pulmonary rehabilitation (PR) on functional parameters and exacerbation rates in patients with chronic obstructive pulmonary disease (COPD). METHODS: A total of 100 patients were enrolled in a multidisciplinary PR program. PR included endurance, resistance and respiratory muscle training. We performed spiroergometry, a modified Bruce Test and measurements of upper and lower limb contractility as well as inspiratory muscle strength before, six and 12 months after beginning rehabilitation. Additionally, we assessed the quality of life and the number of exacerbations and exacerbation days one year before and after starting rehabilitation. RESULTS: 100 patients (42 female/58 male) with COPD (COPD IV-N=36, COPD III-N=42, COPD II-N=22), a mean age of 60.5+/-9.6 years, BMI 25.8+/-6.0 attended a rehabilitation training program over a time period of one year. Spiroergometry (VO2max from 1.1 to 1.3 l/min, P<0.05), modified Bruce Test (from 13+/-7 Min to 18+/-9 Min; P<0.001), upper limb (from 39.9+/-3 to 52.9+/-8 kg; P<0.001) and lower limb strength increased significantly (from 85.3+/-45 to 131.5+/-57 kg; P<0.001). The maximal inspiratory pressure rose from 81.1 mbar to 108.8 mbar (p<0.001). There was no improvement in FEV1 or FEV1/FVC but Saint Georges Respiratory Questionnaire (total score) improved from 37.2+/-3.6 to 26.5+/-2.8; P<0.001. The same was true for exacerbation rates (they dropped from 2.8 to 0.8; P=0.006) and the number of hospitalization days (from 27.3 to 3.3, P<0.001). CONCLUSIONS: One year of outpatient pulmonary rehabilitation is an effective intervention leading to a significant improvement in exercise tolerance and quality of life in patients with COPD also reducing COPD exacerbation rates and hospitalizations.

Heart rate variability and spontaneous baroreflex sequences in supine healthy volunteers subjected to nasal positive airway pressure.

To determine the dynamic effects of short-term nasal positive airway pressure (nPAP) on cardiovascular autonomic control, continuous recordings of noninvasively obtained hemodynamic measurements and heart rate variability (HRV) were obtained in 10 healthy subjects during frequency-controlled breathing (between 0.20 and 0.24 Hz) in supine posture under different pressures of nPAP ranging from 3 to 20 cmH(2)O. HRV was assessed using spectral analysis of the R-R interval. The slope of the regression line between spontaneous systolic blood pressure and pulse interval changes was taken as an index of the sensitivity of arterial baroreflex modulation of heart rate (sequence method). Application of nPAP resulted in a pressure-dependent decrease of cardiac output and stroke volume (P < 0.05, ANOVA) and in an increase in total peripheral resistance (P < 0.03, ANOVA). Hemodynamic changes under increasing nPAP were accompanied by a decrease in total power of HRV despite mean R-R interval remaining unchanged. The overall decrease in HRV was accompanied by a reduction across all frequency bands when absolute units were used (P < 0.01). When the power of low frequency and high frequency was calculated in normalized units, a diminished high frequency and an increased low-to-high frequency ratio were observed (P < 0.05). Compared with low levels of nPAP, pressure levels of >10 cmH(2)O were associated with a significant decline in the mean slope of spontaneous baroreceptor sequences (P < 0.04). These findings indicate that short-term administration of nPAP in normal subjects exerts significant alterations in R-R interval variability and spontaneous baroreflex modulation of heart rate.

Spontaneous bilateral diaphragmatic paralysis: a rare cause of respiratory failure.

Bilateral diaphragmatic paralysis (BDP) can occur in the course of motor neuron disease, myopathy, or from mechanical damage or the use of "ice slush" during cardiac surgery. BDP has been observed during and after infections, associated with systemic lupus erythematosus and mediastinal tumors, or may have idiopathic etiology. It is a serious and life-threatening condition. A 62-yr-old man presented with slowly progressive dyspnoea that worsened in the supine position and on bending forward. Chest X-rays, fluoroscopy, lung-function parameters and blood-gas analysis revealed respiratory failure. BDP was confirmed from a phrenic nerve stimulation test and measurement of transdiaphragmatic pressure (Pdi). Since there was no evidence of an obvious etiology, BDP was considered idiopathic. Other muscles were not involved. The pathological basis was probably focal demyelination in segments of the phrenic nerve. Because of increasing diaphragmatic muscle fatigue, the patient was treated with a nasal mask providing bi-level positive airway pressure (BiPAP) ventilation during the night. Clinical suspicion of BDP should always be raised in patients suffering slowly progressive dyspnoea without any obvious cardiac, metabolic or traumatic predisposing factors, and orthopnoea and dyspnoea on bending forward. Electromyographic tests and measurement of Pdi can reveal the correct diagnosis.

A case of primary tularemic pneumonia presenting with necrotizing mediastinal and hilar lymph nodes.

Tularemia is an unusual disease caused by the gram-negative coccobacillus Francisella tularensis. The clinical features of the disease depend on the route of inoculation. Ulceroglandular and typhoidal forms have been recognized as occurring in tularemia, however primary or secondary pneumonic infections have also been reported. Symptoms, laboratory markers and radiological features are non-specific in tularemic pneumonia. Diagnosis is made on clinical grounds and evidence of elevated agglutinating antibodies to F. tularensis (> 1:128). We report a case of primary tularemic pneumonia presenting with pulmonary infiltrates and necrotizing mediastinal and hilar lymph nodes in an otherwise healthy subject from a non-endemic area. Diagnosis of tularemia was obtained serologically, and antibiotic therapy with doxycycline and streptomycin resolved symptoms and radiological abnormalities. We suggest that tularemia should be considered in the differential diagnosis of pneumonia with mediastinal and/or hilar lymphadenopathy.

Smoking habits of office-based general practitioners and internists in Austria and their smoking cessation efforts.

Tobacco smoking is the major cause of lung disease. This study aimed to determine: 1) the prevalence of tobacco smoking among office-based physicians; 2) their readiness to inquire about their patients' smoking habits and, if need be, to motivate them to stop smoking; 3) whether non-smoking doctors advise their patients more frequently to stop smoking than their smoker colleagues do. A self-designed questionnaire on a post card was sent to 7674 office-based general practitioners (GPs) and internists. 1395 (18.2%) questionnaires were returned. Independent telephone interviews with 91 doctors were also carried out to minimize the bias of self-presentation. Just under 11% of doctors were smokers. About 50% of all doctors who responded described themselves as ex-smokers. 38% of the smokers would accept outside help to stop smoking. About 50% of GPs and 90% of internists inquire about the smoking habits of their patients during history taking. Of these, 85% of GPs and 92% of internists recommend their patients to stop smoking. Doctors who themselves are smokers do so less than their non-smoker colleagues. For this reason, a further reduction in the smoking prevalence among doctors would be of special importance. Inquiry about smoking habits in the initial history taking should be stressed more to identify any smoker who can be subsequently encouraged to stop smoking.