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On the Conditional Power in Survival Time Analysis Considering Cure Fractions.
Genetical Statistics and Systems Biology

Abstract (Expand)

Conditional power of survival endpoints at interim analyses can support decisions on continuing a trial or stopping it for futility. When a cure fraction becomes apparent, conditional power cannot be … calculated accurately using simple survival models, e.g. the exponential model. Non-mixture models consider such cure fractions. In this paper, we derive conditional power functions for non-mixture models, namely the non-mixture exponential, the non-mixture Weibull, and the non-mixture Gamma models. Formulae were implemented in the R package CP. For an example data set of a clinical trial, we calculated conditional power under the non-mixture models and compared results with those under the simple exponential model.

Authors: A. Kuehnapfel, F. Schwarzenberger, M. Scholz

Date Published: 17th Mar 2017

Publication Type: Journal article

Genome-wide meta-analysis identifies novel loci of plaque burden in carotid artery.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND AND AIMS: Carotid artery plaque is an established marker of subclinical atherosclerosis and common patho-mechanisms with coronary artery disease (CAD) are hypothesized. We aimed to identify … genetic variants associated with carotid plaque and to examine the potential shared genetic basis with CAD. METHODS: After investigating the reliability of plaque detection, we performed a genome-wide meta-association study in two independent cohorts (LIFE-Adult, n = 4037 and LIFE-Heart, n = 3152) for carotid plaque score (PS), defined as the sum of the plaque load of common carotid artery and carotid bulb. Further, we analyzed whether previously reported CAD and stroke loci were also associated with PS. RESULTS: We identified two loci with genome-wide significance for PS. One locus is the known CAD-locus at chromosome 9p21 (lead SNP rs9644862, p = 8.73 x 10(-12)). We also describe a novel locus on chromosome 10q24 within the SFXN2 gene as the most probable candidate (lead SNP rs2902548, p = 1.97 x 10(-8)). In addition, 17 out of 58 known CAD loci and six of 17 known stroke loci were associated with PS at a nominal level of significance. CONCLUSIONS: We showed that PS is a reliable trait to analyze genetics of atherosclerosis. Two new loci of genome-wide significant association with PS were found. The observed non-random overlap of CAD and PS associations strengthens the hypothesis of a shared genetic basis for these atherosclerotic manifestations.

Authors: J. Pott, R. Burkhardt, F. Beutner, K. Horn, A. Teren, H. Kirsten, L. M. Holdt, G. Schuler, D. Teupser, M. Loeffler, J. Thiery, M. Scholz

Date Published: 11th Mar 2017

Publication Type: Journal article

Human Diseases: atherosclerosis

Germline Mutations in Triple-Negative Breast Cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and defines a subgroup of patients who do not benefit from endocrine or anti-HER2 therapy. Rather than being a biological entity, … TNBC represents a heterogeneous disease, and further subtyping is necessary to establish targeted therapies. Germline mutational status may serve as a robust biomarker predicting therapy response, especially with respect to compounds challenging the DNA repair machinery. Patients with TNBC usually show an early onset of the disease, as well as a positive family history of breast and/or ovarian cancer in more than one third of all cases, which suggests that TNBC is closely associated with a hereditary disease cause. In unselected TNBC cases, the prevalence of pathogenic germline BRCA1/2 mutations is approximately twice as high as in breast cancer overall. Early age at diagnosis and positive family history are strong predictors for an increased BRCA1/2 mutation probability, which is up to 40% when both risk factors are considered. Apart from BRCA1/2, the rarely mutated breast cancer predisposition genes PALB2 and FANCM have been associated with TNBC. This review summarizes the role of germline mutational status in TNBC pathogenesis. Clinical trials addressing BRCA1/2 mutation carriers are discussed.

Authors: Eric Hahnen, Jan Hauke, Christoph Engel, Guido Neidhardt, Kerstin Rhiem, Rita K. Schmutzler

Date Published: 7th Mar 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Metadata Management for Data Integration in Medical Sciences - Experiences from the LIFE Study -
LIFE - Leipzig Research Center for Civilization Diseases

Abstract (Expand)

Clinical and epidemiological studies are commonly used in medical sciences. They typically collect data by using different input forms and information systems. Metadata describing input forms, database … schemas and input systems are used for data integration but are typically distributed over different software tools; each uses portions of metadata, such as for loading (ETL), data presentation and analysis. In this paper, we describe an approach managing metadata centrally and consistently in a dedicated Metadata Repository (MDR). Metadata can be provided to different tools. Moreover, the MDR includes a matching component creating schema mappings as a prerequisite to integrate captured medical data. We describe the approach, the MDR infrastructure and provide algorithms for creating schema mappings. Finally, we show selected evaluation results. The MDR is fully operational and used to integrate data from a multitude of input forms and systems in the epidemiological study LIFE.

Authors: Toralf Kirsten, A. Kiel, M. Rühle, J.Wagner

Date Published: 2nd Mar 2017

Publication Type: Not specified

Psychometric evaluation of the Generalized Anxiety Disorder Screener GAD-7, based on a large German general population sample.
LIFE Adult

Abstract (Expand)

BACKGROUND: The Generalized Anxiety Disorder Scales GAD-7 and GAD-2 are instruments for the assessment of anxiety. The aims of this study are to test psychometric properties of these questionnaires, … to provide normative values, and to investigate associations with sociodemographic factors, quality of life, psychological variables, and behavioral factors. METHODS: A German community sample (n=9721) with an age range of 18-80 years was surveyed using the GAD-7 and several other questionnaires. RESULTS: Confirmatory factor analyses confirmed the unidimensionality and measurement invariance of the GAD-7 across age and gender. Females were more anxious than males (mean scores: M=4.07 vs. M=3.01; effect size: d=0.33). There was no linear age trend. A total of 5.9% fulfilled the cut-off criterion of 10 and above. Anxiety was correlated with low quality of life, fatigue, low habitual optimism, physical complaints, sleep problems, low life satisfaction, low social support, low education, unemployment, and low income. Cigarette smoking and alcohol consumption were also associated with heightened anxiety, especially in women. When comparing the GAD-7 (7 items) with the ultra-short GAD-2 (2 items), the GAD-7 instrument was superior to the GAD-2 regarding several psychometric criteria. LIMITATIONS: The response rate (33%) was low. Because of the cross-sectional character of the study, causal conclusions cannot be drawn. A further limitation is the lack of a gold standard for diagnosing anxiety. CONCLUSIONS: The GAD-7 can be recommended for use in clinical research and routine.

Authors: A. Hinz, A. M. Klein, E. Brahler, H. Glaesmer, T. Luck, S. G. Riedel-Heller, K. Wirkner, A. Hilbert

Date Published: 1st Mar 2017

Publication Type: Not specified

Human Diseases: generalized anxiety disorder

Predicting brain-age from multimodal imaging data captures cognitive impairment.
LIFE Adult

Abstract (Expand)

The disparity between the chronological age of an individual and their brain-age measured based on biological information has the potential to offer clinically relevant biomarkers of neurological … syndromes that emerge late in the lifespan. While prior brain-age prediction studies have relied exclusively on either structural or functional brain data, here we investigate how multimodal brain-imaging data improves age prediction. Using cortical anatomy and whole-brain functional connectivity on a large adult lifespan sample (N=2354, age 19-82), we found that multimodal data improves brain-based age prediction, resulting in a mean absolute prediction error of 4.29 years. Furthermore, we found that the discrepancy between predicted age and chronological age captures cognitive impairment. Importantly, the brain-age measure was robust to confounding effects: head motion did not drive brain-based age prediction and our models generalized reasonably to an independent dataset acquired at a different site (N=475). Generalization performance was increased by training models on a larger and more heterogeneous dataset. The robustness of multimodal brain-age prediction to confounds, generalizability across sites, and sensitivity to clinically-relevant impairments, suggests promising future application to the early prediction of neurocognitive disorders.

Authors: F. Liem, G. Varoquaux, J. Kynast, F. Beyer, S. Kharabian Masouleh, J. M. Huntenburg, L. Lampe, M. Rahim, A. Abraham, R. C. Craddock, S. Riedel-Heller, T. Luck, M. Loeffler, M. L. Schroeter, A. V. Witte, A. Villringer, D. S. Margulies

Date Published: 1st Mar 2017

Publication Type: Journal article

Sleep quality in the general population: psychometric properties of the Pittsburgh Sleep Quality Index, derived from a German community sample of 9284 people.
LIFE Adult

Abstract (Expand)

BACKGROUND: The Pittsburgh Sleep Quality Index (PSQI) is frequently used to assess sleep problems in patients. The aim of this study was to provide reference values for this questionnaire, to test … psychometric properties, and to analyze associations with psychological, sociodemographic, and behavioral factors. METHODS: A German community sample comprising 9284 adult residents (aged 18-80 years) was surveyed using the PSQI and several other questionnaires. RESULTS: According to the generally accepted cut-off (PSQI > 5), 36% of the general population slept badly. Females reported significantly more sleep problems than males (mean scores: M = 5.5 vs. M = 4.4, respectively; effect size d = 0.35), but there was no linear association between age and sleep quality. Sleep problems were correlated with fatigue, quality of life (physical as well as mental), physical complaints, anxiety, and lack of optimism. Sleep quality was also strongly associated with socioeconomic status, professional situation (poorest sleep quality in unemployed people), and obesity. In addition to the results of the PSQI total score, mean scores of specific components of sleep quality were presented (sleep latency, sleep duration, and use of sleep medication). CONCLUSION: The PSQI proved to be a suitable instrument for measuring sleep quality. Gender differences, psychological factors, and obesity should be taken into account when groups of patients are compared with respect to sleep problems.

Authors: A. Hinz, H. Glaesmer, E. Brahler, M. Loffler, C. Engel, C. Enzenbach, U. Hegerl, C. Sander

Date Published: 21st Feb 2017

Publication Type: Journal article

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