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Sonstige beteiligte Institutionen
Manchia, Mirko ; Adli, Mazda ; Akula, Nirmala ; Arda, Raffaella ; Aubry, Jean-Michel ; Backlund, Lena ; Banzato, Claudio E. M. ; Baune, Bernhard T. ; Bellivier, Frank ; Bengesser, Susanne ; Biernacka, Joanna M. ; Brichant-Petitjean, Clara ; Bui, Elise ; Calkin, Cynthia V. ; Cheng, Andrew Tai Ann ; Chillotti, Caterina ; Cichon, Sven ; Clark, Scott ; Czerski, Piotr M. ; Dantas, Clarissa ; Del Zompo, Maria ; DePaulo, J. Raymond ; Detera-Wadleigh, Sevilla D. ; Etain, Bruno ; Falkai, Peter ; Frisén, Louise ; Frye, Mark A. ; Fullerton, Jan ; Gard, Sébastien ; Garnham, Julie ; Goes, Fernando S. ; Grof, Paul ; Gruber, Oliver ; Hashimoto, Ryota ; Hauser, Joanna ; Heilbronner, Urs ; Hoban, Rebecca ; Hou, Liping ; Jamain, Stéphane ; Kahn, Jean-Pierre ; Kassem, Layla ; Kato, Tadafumi ; Kelsoe, John R. ; Kittel-Schneider, Sarah ; Kliwicki, Sebastian ; Kuo, Po-Hsiu ; Kusumi, Ichiro ; Laje, Gonzalo ; Lavebratt, Catharina ; Leboyer, Marion ; Leckband, Susan G. ; López Jaramillo, Carlos A. ; Maj, Mario ; Malafosse, Alain ; Martinsson, Lina ; Masui, Takuya ; Mitchell, Philip B. ; Mondimore, Frank ; Monteleone, Palmiero ; Nallet, Audrey ; Neuner, Maria ; Novák, Tomás ; O'Donovan, Claire ; Ösby, Urban ; Ozaki, Norio ; Perlis, Roy H. ; Pfennig, Andrea ; Potash, James B. ; Reich-Erkelenz, Daniela ; Reif, Andreas ; Reininghaus, Eva ; Richardson, Sara ; Rouleau, Guy A. ; Rybakowski, Janusz K. ; Schalling, Martin ; Schofield, Peter R. ; Schubert, Oliver K. ; Schweizer, Barbara ; Seemüller, Florian ; Grigoroiu-Serbanescu, Maria ; Severino, Giovanni ; Seymour, Lisa R. ; Slaney, Claire ; Smoller, Jordan W. ; Squassina, Alessio ; Stamm, Thomas ; Steele, Jo ; Stopkova, Pavla ; Tighe, Sarah K. ; Tortorella, Alfonso ; Turecki, Gustavo ; Wray, Naomi R. ; Wright, Adam ; Zandi, Peter P. ; Zilles, David ; Bauer, Michael ; Rietschel, Marcella ; McMahon, Francis J. ; Schulze, Thomas G. ; Alda, Martin
Objective: The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the "Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder" scale currently used in the Consortium on Lithium Genetics (ConLiGen) study.
Materials and Methods: Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (\(\kappa\))] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling.
Results: Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (\(\kappa\) = 0.66 and \(\kappa\) = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (\(ICC_1 = 0.71\) and \(ICC_2 = 0.75\), respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders).
Conclusions: We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study.
Dornelas, Maria ; Antão, Laura H. ; Moyes, Faye ; Bates, Amanda E. ; Magurran, Anne E. ; Adam, Dušan ; Akhmetzhanova, Asem A. ; Appeltans, Ward ; Arcos, José Manuel ; Arnold, Haley ; Ayyappan, Narayanan ; Badihi, Gal ; Baird, Andrew H. ; Barbosa, Miguel ; Barreto, Tiago Egydio ; Bässler, Claus ; Bellgrove, Alecia ; Belmaker, Jonathan ; Benedetti-Cecchi, Lisandro ; Bett, Brian J. ; Bjorkman, Anne D. ; Błażewicz, Magdalena ; Blowes, Shane A. ; Bloch, Christopher P. Bloch ; Bonebrake, Timothy C. ; Boyd, Susan ; Bradford, Matt ; Brooks, Andrew J. ; Brown, James H. ; Bruelheide, Helge ; Budy, Phaedra ; Carvalho, Fernando ; Castañeda-Moya, Edward ; Chen, Chaolun Allen ; Chamblee, John F. ; Chase, Tory J. ; Siegwart Collier, Laura ; Collinge, Sharon K. ; Condit, Richard ; Cooper, Elisabeth J. ; Cornelissen, J. Hans C. ; Cotano, Unai ; Crow, Shannan Kyle ; Damasceno, Gabriella ; Davies, Claire H. ; Davis, Robert A. ; Day, Frank P. ; Degraer, Steven ; Doherty, Tim S. ; Dunn, Timothy E. ; Durigan, Giselda ; Duffy, J. Emmett ; Edelist, Dor ; Edgar, Graham J. ; Elahi, Robin ; Elmendorf, Sarah C. ; Enemar, Anders ; Ernest, S. K. Morgan ; Escribano, Rubén ; Estiarte, Marc ; Evans, Brian S. ; Fan, Tung-Yung ; Turini Farah, Fabiano ; Loureiro Fernandes, Luiz ; Farneda, Fábio Z. ; Fidelis, Alessandra ; Fitt, Robert ; Fosaa, Anna Maria ; Franco, Geraldo Antonio Daher Correa ; Frank, Grace E. ; Fraser, William R. ; García, Hernando ; Cazzolla Gatti, Roberto ; Givan, Or ; Gorgone-Barbosa, Elizabeth ; Gould, William A. ; Gries, Corinna ; Grossman, Gary D. ; Gutierréz, Julio R. ; Hale, Stephen ; Harmon, Mark E. ; Harte, John ; Haskins, Gary ; Henshaw, Donald L. ; Hermanutz, Luise ; Hidalgo, Pamela ; Higuchi, Pedro ; Hoey, Andrew ; Van Hoey, Gert ; Hofgaard, Annika ; Holeck, Kristen ; Hollister, Robert D. ; Holmes, Richard ; Hoogenboom, Mia ; Hsieh, Chih-hao ; Hubbell, Stephen P. ; Huettmann, Falk ; Huffard, Christine L. ; Hurlbert, Allen H. ; Ivanauskas, Natália Macedo ; Janík, David ; Jandt, Ute ; Jażdżewska, Anna ; Johannessen, Tore ; Johnstone, Jill ; Jones, Julia ; Jones, Faith A. M. ; Kang, Jungwon ; Kartawijaya, Tasrif ; Keeley, Erin C. ; Kelt, Douglas A. ; Kinnear, Rebecca ; Klanderud, Kari ; Knutsen, Halvor ; Koenig, Christopher C. ; Kortz, Alessandra R. ; Král, Kamil ; Kuhnz, Linda A. ; Kuo, Chao-Yang ; Kushner, David J. ; Laguionie-Marchais, Claire ; Lancaster, Lesley T. ; Lee, Cheol Min ; Lefcheck, Jonathan S. ; Lévesque, Esther ; Lightfoot, David ; Lloret, Francisco ; Lloyd, John D. ; López-Baucells, Adrià ; Louzao, Maite ; Madin, Joshua S. ; Magnússon, Borgþór ; Malamud, Shahar ; Matthews, Iain ; McFarland, Kent P. ; McGill, Brian ; McKnight, Diane ; McLarney, William O. ; Meador, Jason ; Meserve, Peter L. ; Metcalfe, Daniel J. ; Meyer, Christoph F. J. ; Michelsen, Anders ; Milchakova, Nataliya ; Moens, Tom ; Moland, Even ; Moore, Jon ; Moreira, Carolina Mathias ; Müller, Jörg ; Murphy, Grace ; Myers-Smith, Isla H. ; Myster, Randall W. ; Naumov, Andrew ; Neat, Francis ; Nelson, James A. ; Nelson, Michael Paul ; Newton, Stephen F. ; Norden, Natalia ; Oliver, Jeffrey C. ; Olsen, Esben M. ; Onipchenko, Vladimir G. ; Pabis, Krzysztof ; Pabst, Robert J. ; Paquette, Alain ; Pardede, Sinta ; Paterson, David M. ; Pélissier, Raphaël ; Peñuelas, Josep ; Pérez-Matus, Alejandro ; Pizarro, Oscar ; Pomati, Francesco ; Post, Eric ; Prins, Herbert H. T. ; Priscu, John C. ; Provoost, Pieter ; Prudic, Kathleen L. ; Pulliainen, Erkki ; Ramesh, B. R. ; Ramos, Olivia Mendivil ; Rassweiler, Andrew ; Rebelo, Jose Eduardo ; Reed, Daniel C. ; Reich, Peter B. ; Remillard, Suzanne M. ; Richardson, Anthony J. ; Richardson, J. Paul ; van Rijn, Itai ; Rocha, Ricardo ; Rivera-Monroy, Victor H. ; Rixen, Christian ; Robinson, Kevin P. ; Rodrigues, Ricardo Ribeiro ; de Cerqueira Rossa-Feres, Denise ; Rudstam, Lars ; Ruhl, Henry ; Ruz, Catalina S. ; Sampaio, Erica M. ; Rybicki, Nancy ; Rypel, Andrew ; Sal, Sofia ; Salgado, Beatriz ; Santos, Flavio A. M. ; Savassi-Coutinho, Ana Paula ; Scanga, Sara ; Schmidt, Jochen ; Schooley, Robert ; Setiawan, Fakhrizal ; Shao, Kwang-Tsao ; Shaver, Gaius R. ; Sherman, Sally ; Sherry, Thomas W. ; Siciński, Jacek ; Sievers, Caya ; da Silva, Ana Carolina ; da Silva, Fernando Rodrigues ; Silveira, Fabio L. ; Slingsby, Jasper ; Smart, Tracey ; Snell, Sara J. ; Soudzilovskaia, Nadejda A. ; Souza, Gabriel B. G. ; Souza, Flaviana Maluf ; Souza, Vinícius Castro ; Stallings, Christopher D. ; Stanforth, Rowan ; Stanley, Emily H. ; Sterza, José Mauro ; Stevens, Maarten ; Stuart-Smith, Rick ; Suarez, Yzel Rondon ; Supp, Sarah ; Tamashiro, Jorge Yoshio ; Tarigan, Sukmaraharja ; Thiede, Gary P. ; Thorn, Simon ; Tolvanen, Anne ; Toniato, Maria Teresa Zugliani ; Totland, Ørjan ; Twilley, Robert R. ; Vaitkus, Gediminas ; Valdivia, Nelson ; Vallejo, Martha Isabel ; Valone, Thomas J. ; Van Colen, Carl ; Vanaverbeke, Jan ; Venturoli, Fabio ; Verheye, Hans M. ; Vianna, Marcelo ; Vieira, Rui P. ; Vrška, Tomáš ; Vu, Con Quang ; Vu, Lien Van ; Waide, Robert B. ; Waldock, Conor ; Watts, Dave ; Webb, Sara ; Wesołowski, Tomasz ; White, Ethan P. ; Widdicombe, Claire E. ; Wilgers, Dustin ; Williams, Richard ; Williams, Stefan B. ; Williamson, Mark ; Willig, Michael R. ; Willis, Trevor J. ; Wipf, Sonja ; Woods, Kerry D. ; Woehler, Eric J. ; Zawada, Kyle ; Zettler, Michael L.
Motivation
The BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.
Main types of variables included
The database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.
Spatial location and grain
BioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).
Time period and grain
BioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.
Major taxa and level of measurement
BioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.
Software format
.csv and .SQL.
Frank, Erik Thomas ; Schmitt, Thomas ; Hovestadt, Thomas ; Mitesser, Oliver ; Stiegler, Jonas ; Linsenmair, Karl Eduard
Predators of highly defensive prey likely develop cost-reducing adaptations. The ant Megaponera analis is a specialized termite predator, solely raiding termites of the subfamily Macrotermitinae (in this study, mostly colonies of Pseudocanthotermes sp.) at their foraging sites. The evolutionary arms race between termites and ants led to various defensive mechanisms in termites (for example, a caste specialized in fighting predators). Because M. analis incurs high injury/mortality risks when preying on termites, some risk-mitigating adaptations seem likely to have evolved. We show that a unique rescue behavior in M. analis, consisting of injured nestmates being carried back to the nest, reduces combat mortality. After a fight, injured ants are carried back by their nestmates; these ants have usually lost an extremity or have termites clinging to them and are able to recover within the nest. Injured ants that are forced experimentally to return without help, die in 32% of the cases. Behavioral experiments show that two compounds, dimethyl disulfide and dimethyl trisulfide, present in the mandibular gland reservoirs, trigger the rescue behavior. A model accounting for this rescue behavior identifies the drivers favoring its evolution and estimates that rescuing enables maintenance of a 28.7% larger colony size. Our results are the first to explore experimentally the adaptive value of this form of rescue behavior focused on injured nestmates in social insects and help us to identify evolutionary drivers responsible for this type of behavior to evolve in animals.
Schatton, Tobias ; Yang, Jun ; Kleffel, Sonja ; Uehara, Mayuko ; Barthel, Steven R. ; Schlapbach, Christoph ; Zhan, Qian ; Dudeney, Stephen ; Mueller, Hansgeorg ; Lee, Nayoung ; de Vries, Juliane C. ; Meier, Barbara ; Beken, Seppe Vander ; Kluth, Mark A. ; Ganss, Christoph ; Sharpe, Arlene H. ; Waaga-Gasser, Ana Maria ; Sayegh, Mohamed H. ; Abdi, Reza ; Scharffetter-Kochanek, Karin ; Murphy, George F. ; Kupper, Thomas S. ; Frank, Natasha Y. ; Frank, Markus H.
Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5\(^+\) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5\(^+\) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy.
de Boer, Rudolf A. ; De Keulenaer, Gilles ; Bauersachs, Johann ; Brutsaert, Dirk ; Cleland, John G. ; Diez, Javier ; Du, Xiao-Jun ; Ford, Paul ; Heinzel, Frank R. ; Lipson, Kenneth E. ; McDonagh, Theresa ; Lopez-Andres, Natalia ; Lunde, Ida G. ; Lyon, Alexander R. ; Pollesello, Piero ; Prasad, Sanjay K. ; Tocchetti, Carlo G. ; Mayr, Manuel ; Sluijter, Joost P. G. ; Thum, Thomas ; Tschöpe, Carsten ; Zannad, Faiez ; Zimmermann, Wolfram-Hubertus ; Ruschitzka, Frank ; Filippatos, Gerasimos ; Lindsey, Merry L. ; Maack, Christoph ; Heymans, Stephane
Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction
and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins — resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research.
Schwaneck, Stefan ; Welge, Christopher ; Bopp, Ann-Kathrin ; Faulhaber, Sarah ; Hampel, Susanne ; Pfletschinger, Maike ; Nebelung, Lisa ; Hamme, Berit ; Priddat, Birger ; Salmen, Thomas ; Rosenthal, Georg ; Neumann, Bernd ; Deeg, Steffen ; Buytendijk, Frank ; Gonzalez, Thomas ; Träger, Gloria ; Mayer, Benjamin ; Mohamad, Christoph ; Reinders, Heinz ; Bohmeier, Bernhard
Am Montag, den 29. November 2010 fand das 6. Würzburger Wirtschaftssymposium unter dem Leitmotiv "Chef, lass uns mal Kultur machen!" statt. Die gemeinnützige Veranstaltung versteht sich seit jeher als Ort der Begegnung und des gemeinsamen Gedankenaustauschs, Studenten und Mitarbeiter aller Fachbereiche nahmen ebenso teil wie interessierte Bürger außerhalb der Würzburger Hochschulen. Die Festschrift enthält Interviews mit sowie Gastbeiträge von Referenten des 6. Würzburger Wirtschaftssymposiums. Darüber hinaus greifen Gastbeiträge von Experten aus Wissenschaft, Wirtschaft, Politik und Gesellschaft weitere Facetten auf und stellen das Thema damit auf eine breitere Grundlage.
The ITS2 Database
(2012)
Merget, Benjamin ; Koetschan, Christian ; Hackl, Thomas ; Förster, Frank ; Dandekar, Thomas ; Müller, Tobias ; Schultz, Jörg ; Wolf, Matthias
The internal transcribed spacer 2 (ITS2) has been used as a phylogenetic marker for more than two decades. As ITS2 research mainly focused on the very variable ITS2 sequence, it confined this marker to low-level phylogenetics only. However, the combination of the ITS2 sequence and its highly conserved secondary structure improves the phylogenetic resolution1 and allows phylogenetic inference at multiple taxonomic ranks, including species delimitation.
The ITS2 Database presents an exhaustive dataset of internal transcribed spacer 2 sequences from NCBI GenBank accurately reannotated. Following an annotation by profile Hidden Markov Models (HMMs), the secondary structure of each sequence is predicted. First, it is tested whether a minimum energy based fold (direct fold) results in a correct, four helix conformation. If this is not the case, the structure is predicted by homology modeling. In homology modeling, an already known secondary structure is transferred to another ITS2 sequence, whose secondary structure was not able to fold correctly in a direct fold.
The ITS2 Database is not only a database for storage and retrieval of ITS2 sequence-structures. It also provides several tools to process your own ITS2 sequences, including annotation, structural prediction, motif detection and BLAST search on the combined sequence-structure information. Moreover, it integrates trimmed versions of 4SALE and ProfDistS for multiple sequence-structure alignment calculation and Neighbor Joining tree reconstruction. Together they form a coherent analysis pipeline from an initial set of sequences to a phylogeny based on sequence and secondary structure.
In a nutshell, this workbench simplifies first phylogenetic analyses to only a few mouse-clicks, while additionally providing tools and data for comprehensive large-scale analyses.
Hebestreit, Helge ; Zeidler, Cornelia ; Schippers, Christopher ; de Zwaan, Martina ; Deckert, Jürgen ; Heuschmann, Peter ; Krauth, Christian ; Bullinger, Monika ; Berger, Alexandra ; Berneburg, Mark ; Brandstetter, Lilly ; Deibele, Anna ; Dieris-Hirche, Jan ; Graessner, Holm ; Gündel, Harald ; Herpertz, Stephan ; Heuft, Gereon ; Lapstich, Anne-Marie ; Lücke, Thomas ; Maisch, Tim ; Mundlos, Christine ; Petermann-Meyer, Andrea ; Müller, Susanne ; Ott, Stephan ; Pfister, Lisa ; Quitmann, Julia ; Romanos, Marcel ; Rutsch, Frank ; Schaubert, Kristina ; Schubert, Katharina ; Schulz, Jörg B. ; Schweiger, Susann ; Tüscher, Oliver ; Ungethüm, Kathrin ; Wagner, Thomas O. F. ; Haas, Kirsten
Background
In individuals suffering from a rare disease the diagnostic process and the confirmation of a final diagnosis often extends over many years. Factors contributing to delayed diagnosis include health care professionals' limited knowledge of rare diseases and frequent (co-)occurrence of mental disorders that may complicate and delay the diagnostic process. The ZSE-DUO study aims to assess the benefits of a combination of a physician focusing on somatic aspects with a mental health expert working side by side as a tandem in the diagnostic process.
Study design
This multi-center, prospective controlled study has a two-phase cohort design.
Methods
Two cohorts of 682 patients each are sequentially recruited from 11 university-based German Centers for Rare Diseases (CRD): the standard care cohort (control, somatic expertise only) and the innovative care cohort (experimental, combined somatic and mental health expertise). Individuals aged 12 years and older presenting with symptoms and signs which are not explained by current diagnoses will be included. Data will be collected prior to the first visit to the CRD’s outpatient clinic (T0), at the first visit (T1) and 12 months thereafter (T2).
Outcomes
Primary outcome is the percentage of patients with one or more confirmed diagnoses covering the symptomatic spectrum presented. Sample size is calculated to detect a 10 percent increase from 30% in standard care to 40% in the innovative dual expert cohort. Secondary outcomes are (a) time to diagnosis/diagnoses explaining the symptomatology; (b) proportion of patients successfully referred from CRD to standard care; (c) costs of diagnosis including incremental cost effectiveness ratios; (d) predictive value of screening instruments administered at T0 to identify patients with mental disorders; (e) patients’ quality of life and evaluation of care; and f) physicians’ satisfaction with the innovative care approach.
Conclusions
This is the first multi-center study to investigate the effects of a mental health specialist working in tandem with a somatic expert physician in CRDs. If this innovative approach proves successful, it will be made available on a larger scale nationally and promoted internationally. In the best case, ZSE-DUO can significantly shorten the time to diagnosis for a suspected rare disease.
Breuer, René ; Mattheisen, Manuel ; Frank, Josef ; Krumm, Bertram ; Treutlein, Jens ; Kassem, Layla ; Strohmaier, Jana ; Herms, Stefan ; Mühleisen, Thomas W. ; Degenhardt, Franziska ; Cichon, Sven ; Nöthen, Markus M. ; Karypis, George ; Kelsoe, John ; Greenwood, Tiffany ; Nievergelt, Caroline ; Shilling, Paul ; Shekhtman, Tatyana ; Edenberg, Howard ; Craig, David ; Szelinger, Szabolcs ; Nurnberger, John ; Gershon, Elliot ; Alliey-Rodriguez, Ney ; Zandi, Peter ; Goes, Fernando ; Schork, Nicholas ; Smith, Erin ; Koller, Daniel ; Zhang, Peng ; Badner, Judith ; Berrettini, Wade ; Bloss, Cinnamon ; Byerley, William ; Coryell, William ; Foroud, Tatiana ; Guo, Yirin ; Hipolito, Maria ; Keating, Brendan ; Lawson, William ; Liu, Chunyu ; Mahon, Pamela ; McInnis, Melvin ; Murray, Sarah ; Nwulia, Evaristus ; Potash, James ; Rice, John ; Scheftner, William ; Zöllner, Sebastian ; McMahon, Francis J. ; Rietschel, Marcella ; Schulze, Thomas G.
Background
Disentangling the etiology of common, complex diseases is a major challenge in genetic research. For bipolar disorder (BD), several genome-wide association studies (GWAS) have been performed. Similar to other complex disorders, major breakthroughs in explaining the high heritability of BD through GWAS have remained elusive. To overcome this dilemma, genetic research into BD, has embraced a variety of strategies such as the formation of large consortia to increase sample size and sequencing approaches. Here we advocate a complementary approach making use of already existing GWAS data: a novel data mining procedure to identify yet undetected genotype–phenotype relationships. We adapted association rule mining, a data mining technique traditionally used in retail market research, to identify frequent and characteristic genotype patterns showing strong associations to phenotype clusters. We applied this strategy to three independent GWAS datasets from 2835 phenotypically characterized patients with BD. In a discovery step, 20,882 candidate association rules were extracted.
Results
Two of these rules—one associated with eating disorder and the other with anxiety—remained significant in an independent dataset after robust correction for multiple testing. Both showed considerable effect sizes (odds ratio ~ 3.4 and 3.0, respectively) and support previously reported molecular biological findings.
Conclusion
Our approach detected novel specific genotype–phenotype relationships in BD that were missed by standard analyses like GWAS. While we developed and applied our method within the context of BD gene discovery, it may facilitate identifying highly specific genotype–phenotype relationships in subsets of genome-wide data sets of other complex phenotype with similar epidemiological properties and challenges to gene discovery efforts.
Koehler, Viktoria Florentine ; Adam, Pia ; Fuss, Carmina Teresa ; Jiang, Linmiao ; Berg, Elke ; Frank-Raue, Karin ; Raue, Friedhelm ; Hoster, Eva ; Knösel, Thomas ; Schildhaus, Hans-Ulrich ; Negele, Thomas ; Siebolts, Udo ; Lorenz, Kerstin ; Allelein, Stephanie ; Schott, Matthias ; Spitzweg, Christine ; Kroiss, Matthias
Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.