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Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. …. METHODS We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. RESULTS There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 \times 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 \times 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 \times 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 \times 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 \times 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

Authors: Nasim Mavaddat, Daniel Barrowdale, Irene L. Andrulis, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Amanda Spurdle, Mark Robson, Mark Sherman, Anna Marie Mulligan, Fergus J. Couch, Christoph Engel, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Melissa C. Southey, Mary Beth Terry, David Goldgar, Frances O’Malley, Esther M. John, Ramunas Janavicius, Laima Tihomirova, Thomas v. O. Hansen, Finn C. Nielsen, Ana Osorio, Alexandra Stavropoulou, Javier Benítez, Siranoush Manoukian, Bernard Peissel, Monica Barile, Sara Volorio, Barbara Pasini, Riccardo Dolcetti, Anna Laura Putignano, Laura Ottini, Paolo Radice, Ute Hamann, Muhammad U. Rashid, Frans B. Hogervorst, Mieke Kriege, Rob B. van der Luijt, Susan Peock, Debra Frost, D. Gareth Evans, Carole Brewer, Lisa Walker, Mark T. Rogers, Lucy E. Side, Catherine Houghton, JoEllen Weaver, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Karin Kast, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Doroteha Gadzicki, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schönbuchner, Heidrun Gevensleben, Dominique Stoppa-Lyonnet, Muriel Belotti, Laure Barjhoux, Claudine Isaacs, Beth N. Peshkin, Trinidad Caldes, Miguel de La Hoya, Carmen Cañadas, Tuomas Heikkinen, Päivi Heikkilä, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Bjarni A. Agnarsson, Adalgeir Arason, Rosa B. Barkardottir, Martine Dumont, Jacques Simard, Marco Montagna, Simona Agata, Emma D’Andrea, Max Yan, Stephen Fox, Timothy R. Rebbeck, Wendy Rubinstein, Nadine Tung, Judy E. Garber, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia M. Gaudet, Christian F. Singer, Muy-Kheng Tea, Christine Rappaport, Phuong L. Mai, Mark H. Greene, Anna Sokolenko, Evgeny Imyanitov, Amanda Ewart Toland, Leigha Senter, Kevin Sweet, Mads Thomassen, Anne-Marie Gerdes, Torben Kruse, Maria Caligo, Paolo Aretini, Johanna Rantala, Anna von Wachenfeld, Karin Henriksson, Linda Steele, Susan L. Neuhausen, Robert Nussbaum, Mary Beattie, Kunle Odunsi, Lara Sucheston, Simon A. Gayther, Kate Nathanson, Jenny Gross, Christine Walsh, Beth Karlan, Georgia Chenevix-Trench, Douglas F. Easton, Antonis C. Antoniou

Date Published: 5th Jan 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require …e interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer. METHODS We tested the performance of four prediction tools (Align-GVGD, SIFT, PolyPhen-2, MutationTaster2) using a set of 236 BRCA1/2 missense variants that had previously been classified by expert committees. However, a major pitfall in the creation of a reliable evaluation set for our purpose is the generally accepted classification of BRCA1/2 missense variants using the multifactorial likelihood model, which is partially based on Align-GVGD results. To overcome this drawback we identified 161 variants whose classification is independent of any previous in silico prediction. In addition to the performance as stand-alone tools we examined the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of combined approaches. RESULTS PolyPhen-2 achieved the lowest sensitivity (0.67), specificity (0.67), accuracy (0.67) and MCC (0.39). Align-GVGD achieved the highest values of specificity (0.92), accuracy (0.92) and MCC (0.73), but was outperformed regarding its sensitivity (0.90) by SIFT (1.00) and MutationTaster2 (1.00). All tools suffered from poor specificities, resulting in an unacceptable proportion of false positive results in a clinical setting. This shortcoming could not be bypassed by combination of these tools. In the best case scenario, 138 families would be affected by the misclassification of neutral variants within the cohort of patients of the German Consortium for Hereditary Breast and Ovarian Cancer. CONCLUSION We show that due to low specificities state-of-the-art in silico prediction tools are not suitable to predict pathogenicity of variants of uncertain significance in BRCA1/2. Thus, clinical consequences should never be based solely on in silico forecasts. However, our data suggests that SIFT and MutationTaster2 could be suitable to predict benignity, as both tools did not result in false negative predictions in our analysis.

Authors: Corinna Ernst, Eric Hahnen, Christoph Engel, Michael Nothnagel, Jonas Weber, Rita K. Schmutzler, Jan Hauke

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

PET/MR in dementia and other neurodegenerative diseases.
LIFE Adult

Abstract (Expand)

The spectrum of neurodegenerative diseases covers the dementias, parkinsonian syndromes, Huntington disease, amyotrophic lateral sclerosis, and prion diseases. In these entities, brain MRI is often … used in clinical routine to exclude other pathologies and to demonstrate specific atrophy patterns. [18F]FDG PET delivers early and sensitive readouts of neural tissue loss, and more specific PET tracers currently in use clinically target beta-amyloid plaques or dopaminergic deficiency. The recent integration of PET into MR technology offers a new chance to improve early and differential diagnosis of many neurodegenerative diseases. Initial evidence in the literature is available to support this notion. New emerging PET tracers, such as tracers that bind to tau or alpha-synuclein aggregates, as well as MR techniques, like diffusion-tensor imaging, resting-state functional MRI, and arterial spin labeling, have the potential to broaden the diagnostic capabilities of combined PET/MRI to image dementias, Parkinson disease, and other neurodegenerative diseases. The ultimate goal is to establish combined PET/MRI as a first-line imaging technique to provide, in a one-stop-shop fashion with improved patient comfort, all biomarker information required to increase diagnostic confidence toward specific diagnoses. The technical challenge of accurate PET data attenuation correction within PET/MRI systems needs yet to be solved. Apart from the projected clinical routine applications, future research would need to answer the questions of whether combined brain PET/MRI is able to improve basic research of neurodegenerative diseases and antineurodegeneration drug testing.

Authors: H. Barthel, M. L. Schroeter, K. T. Hoffmann, O. Sabri

Date Published: 6th Apr 2015

Publication Type: Not specified

Human Diseases: dementia, neurodegenerative disease

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for … prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Authors: Nasim Mavaddat, Kyriaki Michailidou, Joe Dennis, Michael Lush, Laura Fachal, Andrew Lee, Jonathan P. Tyrer, Ting-Huei Chen, Qin Wang, Manjeet K. Bolla, Xin Yang, Muriel A. Adank, Thomas Ahearn, Kristiina Aittomäki, Jamie Allen, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Päivi Auvinen, Myrto Barrdahl, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Michael Bremer, Hermann Brenner, Adam Brentnall, Ian W. Brock, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Daniele Campa, Brian D. Carter, Jose E. Castelao, Stephen J. Chanock, Rowan Chlebowski, Hans Christiansen, Christine L. Clarke, J. Margriet Collée, Emilie Cordina-Duverger, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Asta Försti, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Irina R. Gilyazova, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Steven N. Hart, Wei He, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Katarzyna Kaczmarek, Vesa Kataja, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Julia A. Knight, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Jenna Lilyquist, Annika Lindblom, Sara Lindström, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Usha Menon, Pooja Middha, Nicola Miller, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Victor M. Muñoz-Garzon, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Kenneth Offit, Janet E. Olson, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I. A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Julian Peto, Mila Pinchev, Dijana Plaseska-Karanfilska, Eric C. Polley, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Kristen Purrington, Katri Pylkäs, Brigitte Rack, Paolo Radice, Rohini Rau-Murthy, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Mark Robson, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Caroline Seynaeve, Mitul Shah, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Susan Slager, Ann Smeets, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Jennifer Stone, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Maria Tzardi, Hans-Ulrich Ulmer, Michael Untch, Celine M. Vachon, Elke M. van Veen, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Deborah J. Thompson, Georgia Chenevix-Trench, Jenny Chang-Claude, Marjanka K. Schmidt, Per Hall, Roger L. Milne, Paul D. P. Pharoah, Antonis C. Antoniou, Nilanjan Chatterjee, Peter Kraft, Montserrat García-Closas, Jacques Simard, Douglas F. Easton

Date Published: 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine … mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5’ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Authors: Hatef Darabi, Karen McCue, Jonathan Beesley, Kyriaki Michailidou, Silje Nord, Siddhartha Kar, Keith Humphreys, Deborah Thompson, Maya Ghoussaini, Manjeet K. Bolla, Joe Dennis, Qin Wang, Sander Canisius, Christopher G. Scott, Carmel Apicella, John L. Hopper, Melissa C. Southey, Jennifer Stone, Annegien Broeks, Marjanka K. Schmidt, Rodney J. Scott, Artitaya Lophatananon, Kenneth Muir, Matthias W. Beckmann, Arif B. Ekici, Peter A. Fasching, Katharina Heusinger, Isabel Dos-Santos-Silva, Julian Peto, Ian Tomlinson, Elinor J. Sawyer, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E. Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L. Neuhausen, Volker Arndt, Hermann Brenner, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Norbert Arnold, Hiltrud Brauch, Ute Hamann, Jenny Chang-Claude, Sofia Khan, Heli Nevanlinna, Hidemi Ito, Keitaro Matsuo, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Veli-Matti Kosma, Arto Mannermaa, Chiu-Chen Tseng, Anna H. Wu, Giuseppe Floris, Diether Lambrechts, Anja Rudolph, Paolo Peterlongo, Paolo Radice, Fergus J. Couch, Celine Vachon, Graham G. Giles, Catriona McLean, Roger L. Milne, Pierre-Antoine Dugué, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Brian E. Henderson, Mark S. Goldberg, Jacques Simard, Soo H. Teo, Shivaani Mariapun, Åslaug Helland, Vilde Haakensen, Wei Zheng, Alicia Beeghly-Fadiel, Rulla Tamimi, Arja Jukkola-Vuorinen, Robert Winqvist, Irene L. Andrulis, Julia A. Knight, Peter Devilee, Robert A. E. M. Tollenaar, Jonine Figueroa, Montserrat García-Closas, Kamila Czene, Maartje J. Hooning, Madeleine Tilanus-Linthorst, Jingmei Li, Yu-Tang Gao, Xiao-Ou Shu, Angela Cox, Simon S. Cross, Robert Luben, Kay-Tee Khaw, Ji-Yeob Choi, Daehee Kang, Mikael Hartman, Wei Yen Lim, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, James McKay, Suleeporn Sangrajrang, Amanda E. Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Jyh-Cherng Yu, Argyrios Ziogas, Minouk J. Schoemaker, Anthony Swerdlow, Anne-Lise Borresen-Dale, Vessela Kristensen, Juliet D. French, Stacey L. Edwards, Alison M. Dunning, Douglas F. Easton, Per Hall, Georgia Chenevix-Trench

Date Published: 1st Jul 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Polymorphisms in BRCA2 resulting in aberrant codon-usage and their analysis on familial breast cancer risk
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Mutations in BRCA1 and BRCA2 are associated with increased breast cancer risk. While numerous non-synonymous SNPs in BRCA1/2 have been investigated for breast cancer risk, the impact of synonymous SNPs … has not been studied so far. Recently, it has been reported that synonymous SNPs leading to an aberration from the preferred codon-usage can have functional effects and consequently be associated with disease. This motivated us to search for SNPs with the tendency to differential codon-usage in BRCA1/BRCA2. Based on defined criteria, two codon-usage-changing variants, Ser455Ser (1365A \textgreater G) and Ser2414Ser (7242A \textgreater G), were detected in BRCA2, whereas no such variant could be identified in BRCA1. We investigated the impact of these variants on breast cancer risk in a large case-control study. However, both SNPs, BRCA2 Ser2414Ser (7242A \textgreater G) and Ser455Ser (1365A \textgreater G), showed no association with breast cancer risk. This indicates that these codon-usage-changing SNPs have no major impact on familial breast cancer risk.

Authors: Rongxi Yang, Bowang Chen, Kari Hemminki, Barbara Wappenschmidt, Christoph Engel, Christian Sutter, Nina Ditsch, Bernhard H. F. Weber, Dieter Niederacher, Norbert Arnold, Alfons Meindl, Claus R. Bartram, Rita K. Schmutzler, Barbara Burwinkel

Date Published: 1st Nov 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Practice and perception–a nationwide survey of therapy habits in sepsis
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. DESIGN One-day cross-sectional survey. SETTING …TING Representative sample of German intensive care units stratified by hospital size. PATIENTS Adult patients with severe sepsis or septic shock. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses \textquotedblalways\textquotedbl and \textquotedblfrequently\textquotedbl were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation \textless or = 6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% \textgreater 8 mL/kg predicted body weight. Mean tidal volume was 10.0 +/- 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4-6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels \textless or = 8.3 mmol/L and 66.2% were hyperglycemic (blood glucose \textgreater 8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels \textless or = 8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 +/- 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. CONCLUSIONS This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Authors: Frank M. Brunkhorst, Christoph Engel, Max Ragaller, Tobias Welte, Rolf Rossaint, Herwig Gerlach, Konstantin Mayer, Stefan John, Frank Stuber, Norbert Weiler, Michael Oppert, Onnen Moerer, Holger Bogatsch, Konrad Reinhart, Markus Loeffler, Christiane Hartog

Date Published: 2008

Publication Type: Journal article

Human Diseases: disease by infectious agent

Practice of volume therapy in patients with severe sepsis: results from a nationwide sepsis prevalence study
SepNet - German Competence Network Sepsis

Abstract

Not specified

Authors: Christiane S. Hartog, Frank M. Brunkhorst, Frank Bloos, Holger Bogatsch, Christoph Engel, Kerstin Sengebusch, Konrad Reinhart, Maximilian Ragaller

Date Published: 1st Mar 2010

Publication Type: Journal article

Human Diseases: disease by infectious agent

Predicting behavioral variant frontotemporal dementia with pattern classification in multi-center structural MRI data.
LIFE Adult

Abstract (Expand)

PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early onset dementia. Behavioral variant frontotemporal dementia (bvFTD), its most common subtype, is characterized by deep … alterations in behavior and personality. In 2011, new diagnostic criteria were suggested that incorporate imaging criteria into diagnostic algorithms. The study aimed at validating the potential of imaging criteria to individually predict diagnosis with machine learning algorithms. MATERIALS & METHODS: Brain atrophy was measured with structural magnetic resonance imaging (MRI) at 3 Tesla in a multi-centric cohort of 52 bvFTD patients and 52 healthy control subjects from the German FTLD Consortium's Study. Beside group comparisons, diagnosis bvFTD vs. controls was individually predicted in each subject with support vector machine classification in MRI data across the whole brain or in frontotemporal, insular regions, and basal ganglia known to be mainly affected based on recent meta-analyses. Multi-center effects were controlled for with a new method, "leave one center out" conjunction analyses, i.e. repeatedly excluding subjects from each center from the analysis. RESULTS: Group comparisons revealed atrophy in, most consistently, the frontal lobe in bvFTD beside alterations in the insula, basal ganglia and temporal lobe. Most remarkably, support vector machine classification enabled predicting diagnosis in single patients with a high accuracy of up to 84.6%, where accuracy was highest in a region-of-interest approach focusing on frontotemporal, insular regions, and basal ganglia in comparison with the whole brain approach. CONCLUSION: Our study demonstrates that MRI, a widespread imaging technology, can individually identify bvFTD with high accuracy in multi-center imaging data, paving the road to personalized diagnostic approaches in the future.

Authors: S. Meyer, K. Mueller, K. Stuke, S. Bisenius, J. Diehl-Schmid, F. Jessen, J. Kassubek, J. Kornhuber, A. C. Ludolph, J. Prudlo, A. Schneider, K. Schuemberg, I. Yakushev, M. Otto, M. L. Schroeter

Date Published: 29th Mar 2017

Publication Type: Journal article

Human Diseases: frontotemporal dementia

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

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first … time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 \times 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 \times 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Authors: Julie Lecarpentier, Valentina Silvestri, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Penny Soucy, Goska Leslie, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, Andrew Lee, Ali Amin Al Olama, Jonathan P. Tyrer, Melissa Southey, Esther M. John, Thomas A. Conner, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, Thomas v. O. Hansen, Ana Osorio, Jeffrey N. Weitzel, Angela Toss, Veronica Medici, Laura Cortesi, Ines Zanna, Domenico Palli, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Alessandra Viel, Giulia Cini, Giuseppe Damante, Stefania Tommasi, Paolo Peterlongo, Florentia Fostira, Ute Hamann, D. Gareth Evans, Alex Henderson, Carole Brewer, Diana Eccles, Jackie Cook, Kai-Ren Ong, Lisa Walker, Lucy E. Side, Mary E. Porteous, Rosemarie Davidson, Shirley Hodgson, Debra Frost, Julian Adlard, Louise Izatt, Ros Eeles, Steve Ellis, Marc Tischkowitz, Andrew K. Godwin, Alfons Meindl, Andrea Gehrig, Bernd Dworniczak, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Eric Hahnen, Jan Hauke, Kerstin Rhiem, Karin Kast, Norbert Arnold, Nina Ditsch, Shan Wang-Gohrke, Barbara Wappenschmidt, Dorothea Wand, Christine Lasset, Dominique Stoppa-Lyonnet, Muriel Belotti, Francesca Damiola, Laure Barjhoux, Sylvie Mazoyer, Mattias van Heetvelde, Bruce Poppe, Kim de Leeneer, Kathleen B. M. Claes, Miguel de La Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, Pedro Perez Segura, Johanna I. Kiiski, Kristiina Aittomäki, Sofia Khan, Heli Nevanlinna, Christi J. van Asperen, Tibor Vaszko, Miklos Kasler, Edith Olah, Judith Balmaña, Sara Gutiérrez-Enríquez, Orland Diez, Alex Teulé, Angel Izquierdo, Esther Darder, Joan Brunet, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, Conxi Lazaro, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th Johannsson, Rosa B. Barkardottir, Elisa Alducci, Silvia Tognazzo, Marco Montagna, Manuel R. Teixeira, Pedro Pinto, Amanda B. Spurdle, Helene Holland, Jong Won Lee, Min Hyuk Lee, Jihyoun Lee, Sung-Won Kim, Eunyoung Kang, Zisun Kim, Priyanka Sharma, Timothy R. Rebbeck, Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, Yen Y. Tan, Andreas Berger, Christian F. Singer, Jennifer T. Loud, Mark H. Greene, Anna Marie Mulligan, Gord Glendon, Irene L. Andrulis, Amanda Ewart Toland, Leigha Senter, Anders Bojesen, Henriette Roed Nielsen, Anne-Bine Skytte, Lone Sunde, Uffe Birk Jensen, Inge Sokilde Pedersen, Lotte Krogh, Torben A. Kruse, Maria A. Caligo, Sook-Yee Yoon, Soo-Hwang Teo, Anna von Wachenfeldt, Dezheng Huo, Sarah M. Nielsen, Olufunmilayo I. Olopade, Katherine L. Nathanson, Susan M. Domchek, Christa Lorenchick, Rachel C. Jankowitz, Ian Campbell, Paul James, Gillian Mitchell, Nick Orr, Sue Kyung Park, Mads Thomassen, Kenneth Offit, Fergus J. Couch, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Rita K. Schmutzler, Antonis C. Antoniou, Laura Ottini

Date Published: 10th Jul 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE: To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. PATIENTS AND METHODS: Data from 21 401 … families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. RESULTS: The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). CONCLUSIONS: Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.

Authors: K. Kast, K. Rhiem, B. Wappenschmidt, E. Hahnen, J. Hauke, B. Bluemcke, V. Zarghooni, N. Herold, N. Ditsch, M. Kiechle, M. Braun, C. Fischer, N. Dikow, S. Schott, N. Rahner, D. Niederacher, T. Fehm, A. Gehrig, C. Mueller-Reible, N. Arnold, N. Maass, G. Borck, N. de Gregorio, C. Scholz, B. Auber, R. Varon-Manteeva, D. Speiser, J. Horvath, N. Lichey, P. Wimberger, S. Stark, U. Faust, B. H. Weber, G. Emons, S. Zachariae, A. Meindl, R. K. Schmutzler, C. Engel

Date Published: 2nd Mar 2016

Publication Type: Journal article

Human Diseases: breast cancer, ovarian cancer

Prevalence of minor depression in elderly persons with and without mild cognitive impairment: a systematic review.
LIFE Adult

Abstract (Expand)

BACKGROUND: Minor depression (MinD) and mild cognitive impairment (MCI) are common disorders in late life that often coexist. The aim of the present review is to demonstrate prevalence rates of minor … depression in older patients with and without MCI. METHODS: Electronic database searches were performed through Medline, ISI Web of Knowledge, Psycinfo, and Cochrane library. Two independent reviewers extracted the original studies based on inclusion criteria: representative study population aged 55 and older, diagnostics of MinD according to DSM. Data on prevalence rates, risk factors, comorbidity and health care usage were analyzed. RESULTS: Point prevalence for MinD is higher in medical settings (median 14.4%) than in the community-based settings (median 10.4%) and primary care patients (median 7.7%). Although minor depression is rarely investigated in elderly persons with MCI, nearly 20% of patients with MCI seem to suffer from MinD. No data was found on the prevalence of MCI in patients with MinD. Risk factors associated with MinD include female gender, history of cerebrovascular diseases, generalized anxiety disorder, loneliness, and long-term institutional care. LIMITATIONS: Methodological differences of included studies resulted in a broad range of prevalence rates. No data is shown regarding the prevalence of MCI in MinD group due to insufficient evidence. CONCLUSIONS: Our review indicates that MinD is frequent in elderly population. MCI among those subjects has not been sufficiently investigated. Future studies based on clinical structured interviews should be performed in longitudinal design in order to differentiate late-life depression from progressive MCI or early manifestation of Alzheimer's disease.

Authors: M. Polyakova, N. Sonnabend, C. Sander, R. Mergl, M. L. Schroeter, J. Schroeder, P. Schonknecht

Date Published: 10th Oct 2013

Publication Type: Not specified

Human Diseases: mental depression

Prevalence of moderately increased albuminuria among individuals with normal HbA1c level but impaired glucose tolerance: Results from the LIFE-Adult-Study.
LIFE Adult

Abstract (Expand)

Aims: Diabetes screening strategies using glycated haemoglobin (HbA1c) as first-instance diagnostic parameter may cause failure to detect individuals with abnormal glucose regulation and possible signs … of microvascular complications despite "rule-out" HbA1c levels. This cross-sectional study examined the diagnostic performance of HbA1c in relation to fasting and two-hour postload plasma glucose (FPG/2 h-PG), and investigated whether individuals with normal HbA1c but abnormal FPG/2 h-PG have a higher prevalence of moderately increased albuminuria as possible sign of early stage kidney damage. Methods: A total of 2695 individuals (age 40-79 years, 48% men) without prior diagnosis of diabetes and complete measurement of HbA1c, FPG, 2 h-PG and urine albumin-creatinine ratio (UACR) were taken from a large population-based epidemiological study in the City of Leipzig, Germany. Results: A total of 2439 individuals (90.5%, 95% CI: 89.4-91.6) had normal HbA1c levels, <39 mmol/mol (<5.7%), while 234 (8.7%, 95% CI: 7.7-9.8) had prediabetes, HbA1c >/=39 and <48 mmol/mol (>/=5.7 and <6.5%), and 22 (0.8%, 95% CI: 0.5-1.2) had diabetes, HbA1c >/=48 mmol/mol (>/=6.5%), according to HbA1c. Among individuals with normal HbA1c, 35.6% (95% CI: 33.7-37.5) had impaired fasting glucose or impaired glucose tolerance and 1.8% (95% CI: 1.4-2.4) had diabetes according to FPG/2 h-PG. Individuals with normal HbA1c but prediabetic or diabetic FPG/2 h-PG had a significantly higher prevalence of moderately increased albuminuria (9.4%, 95% CI: 7.6-11.5 and 13.3%, 95% CI: 5.8-25.4, respectively) than individuals with normal HbA1c and normal FPG/2 h-PG (3.9%, 95% CI: 3.0-5.0). Conclusions: The prevalence of prediabetes according to FPG/2 h-PG among individuals with normal HbA1c is considerably high, and the prevalence of moderately increased albuminuria in this group is significantly elevated. Risk factors for diabetes such as age, gender and BMI may help to better identify this at-risk group.

Authors: M. Zivkovic, A. Tonjes, R. Baber, K. Wirkner, M. Loeffler, C. Engel

Date Published: 1st Mar 2019

Publication Type: Not specified

Human Diseases: glucose metabolism disease

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic …c testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. METHODS The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. RESULTS A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p \textless 0.001). gBRCA mutation risk was predicted to be \textgreater 10% for women diagnosed below approximately 50 years. CONCLUSIONS Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Authors: Christoph Engel, Kerstin Rhiem, Eric Hahnen, Sibylle Loibl, Karsten E. Weber, Sabine Seiler, Silke Zachariae, Jan Hauke, Barbara Wappenschmidt, Anke Waha, Britta Blümcke, Marion Kiechle, Alfons Meindl, Dieter Niederacher, Claus R. Bartram, Dorothee Speiser, Brigitte Schlegelberger, Norbert Arnold, Peter Wieacker, Elena Leinert, Andrea Gehrig, Susanne Briest, Karin Kast, Olaf Riess, Günter Emons, Bernhard H. F. Weber, Jutta Engel, Rita K. Schmutzler

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Progesterone mediates brain functional connectivity changes during the menstrual cycle-a pilot resting state MRI study.
LIFE Adult

Abstract (Expand)

The growing interest in intrinsic brain organization has sparked various innovative approaches to generating comprehensive connectivity-based maps of the human brain. Prior reports point to a sexual … dimorphism of the structural and functional human connectome. However, it is uncertain whether subtle changes in sex hormones, as occur during the monthly menstrual cycle, substantially impact the functional architecture of the female brain. Here, we performed eigenvector centrality (EC) mapping in 32 longitudinal resting state fMRI scans of a single healthy subject without oral contraceptive use, across four menstrual cycles, and assessed estrogen and progesterone levels. To investigate associations between cycle-dependent hormones and brain connectivity, we performed correlation analyses between the EC maps and the respective hormone levels. On the whole brain level, we found a significant positive correlation between progesterone and EC in the bilateral dorsolateral prefrontal cortex (DLPFC) and bilateral sensorimotor cortex. In a secondary region-of-interest analysis, we detected a progesterone-modulated increase in functional connectivity of both bilateral DLPFC and bilateral sensorimotor cortex with the hippocampus. Our results suggest that the menstrual cycle substantially impacts intrinsic functional connectivity, particularly in brain areas associated with contextual memory-regulation, such as the hippocampus. These findings are the first to link the subtle hormonal fluctuations that occur during the menstrual cycle, to significant changes in regional functional connectivity in the hippocampus in a longitudinal design, given the limitation of data acquisition in a single subject. Our study demonstrates the feasibility of such a longitudinal Resting-state functional Magnetic Resonance Imaging (rs-fMRI) design and illustrates a means of creating a personalized map of the human brain by integrating potential mediators of brain states, such as menstrual cycle phase.

Authors: K. Arelin, K. Mueller, C. Barth, P. V. Rekkas, J. Kratzsch, I. Burmann, A. Villringer, J. Sacher

Date Published: 11th Mar 2015

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

Psychometric properties of the Satisfaction with Life Scale (SWLS), derived from a large German community sample.
LIFE Adult

Abstract (Expand)

PURPOSE: The aim of this study was to test psychometric properties of the Satisfaction with Life Scale (SWLS), to provide normative values, and to analyze associations between life satisfaction and … sociodemographic and behavioral data. METHODS: A German community sample (n = 9711) with an age range of 18-80 years was surveyed using the SWLS and several other questionnaires. Confirmatory factor analysis (CFA) was used to test the dimensionality of the SWLS. Invariance across gender and age groups was tested with multiple-group CFA. Associations between SWLS, sociodemographic variables, and behavioral variables were tested with ANOVAs. RESULTS: Confirmatory factorial analysis results confirmed that the SWLS is a one-dimensional scale. Measurement invariance across gender was completely confirmed, while concerning age strict measurement invariance was confirmed. The effects of gender and age on satisfaction with life were weak. Satisfaction with life was associated with fatigue (r = - .49), the mental component of quality of life (r = .45), anxiety (r = - .42), dispositional optimism (r = .41), pessimism (r = - .34), sleep quality (r = - .32), and sociodemographic factors such as marital status, income, and occupational status. Non-smokers reported higher life satisfaction than smokers. CONCLUSIONS: Because of the good psychometric properties, the SWLS can be recommended for use in epidemiological research. Normative values based on a large community sample are provided.

Authors: A. Hinz, I. Conrad, M. L. Schroeter, H. Glaesmer, E. Brahler, M. Zenger, R. D. Kocalevent, P. Y. Herzberg

Date Published: 29th Mar 2018

Publication Type: Not specified

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