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Dr. Clemens Kreutz


Institute of Medical Biometry and Statistics (IMBI)
Freiburg Center for Data Analysis and Modeling (FDM)
Faculty of Medicine and Medical Center

Methods of Modelling and Bioinformatics in Systems Biomedicine (MSB)
 - Unit head -

Stefan-Meier-Str. 26
79104 Freiburg

Photo - Clemens Kreutz 
E-mail: ckreutz@imbi.uni-freiburg.de
Phone: ++49 (0)761 203-54281
Fax: ++49 (0)761 203-6680
MSB, Stefan-Meier-Str. 26
Room no.: -1.027

Research Interests

  • Development of new algorithms and statistical approaches
  • Mathematical modelling of biochemical reaction networks
  • Benchmarking
  • Machine learning/deep learning for classification, prediction and pattern recognition
  • Analysis of complex and high-dimensional data
  • Uncertainty analyses
  • Experimental design
  • Transcriptomics, proteomics, cytometry, imaging
  • Cancer
  • Insulin-, growth factor-, apoptotic- and TGFb signal transduction
  • Linking signal transduction, genomics and transcription to phenotype
  • Biomarker
  • Selection and optimization of algorithms for specific application settings

Projects

Projects

 

 
Publications
 

 

B. Steiert, C. Kreutz, J. Timmer
Recipes for Analysis of Molecular Networks Using the Data2Dynamics Modeling Environment
Hlavacek W. (eds) Modeling Biomolecular Site Dynamics. Methods in Molecular Biology, vol 1945. Humana Press, New York, 2019.

S. Bernhardt, C. Toensing, D. Mitra, N. Erdem, K. Mueller-Decker, U. Korf, C. Kreutz, J. Timmer, S. Wiemann
Functional proteomics of breast cancer metabolism identifies GLUL as responder during hypoxic adaptation
J. Proteome Res, 2019, 18, 3, 1352-1362.

H. Hass, C. Loos, E. Raimundez Alvarez, J. Timmer, J. Hasenauer, C. Kreutz
Benchmark Problems for Dynamic Modeling of Intracellular Processes
Bioinformatics, btz020, 2019, accepted.
BioRxiv preprint version

K. Becker, A. Bluhm, N. Casas-Vila, N. Dinges, M. Dejung, S. Sayols, C. Kreutz, J. Roignant, F. Butter, S. Legewie
Quantifying post-transcriptional regulation in the development of Drosophila melanogaster
Nature Communications, 9: 4980, 1-14, 2018.

R. Seitz-Alghrouz, J. Hidalgo, C. Kayser, C. Kreutz, K. Technau-Hafsi, C. Diaz, A. von Deimling, J. Timmer, M. Werner, M. Malkovsky, P. Fisch
BRAF V600E Mutations in Nevi and Melanocytic Tumors of Uncertain Malignant Potential (MELTUMPs)
Journal of Investigative Dermatology, 2018, 138(11), 2489-2491.

C. Kreutz
An easy and efficient approach for testing identifiability of parameters.
Bioinformatics, 34(11), 1913-1921, 2018.
arXiv-preprint (Aug, 2017)

P. Lucarelli, M. Schilling, C. Kreutz, A. Vlasov, M. Boehm, N. Iwamoto, B. Steiert, S. Lattermann, M. Waesch, M. Stepath, M. Matter, M. Heikenwaelder, K. Hoffmann, D. Deharde, G. Damm, D. Seehofer, M. Muciek, N. Gretz, W. Lehmann, J. Timmer, U. Klingmueller
Resolving the Combinatorial Complexity of Smad Protein Complex Formation and the Link to Gene Expression
Cell Systems, 2018, 24;6(1):75-89.e11.

C. Toensing, C. Kreutz, J. Timmer
Profile likelihood based analyses of infectious disease models.
Statistical Methods in Medical Research, 2018, 27(7), 1979-1998.

C. Kreutz, S. MacNelly, M. Follo, A. Waeldin, P. Binninger-Lacour, J. Timmer, M. Bartolome Rodriguez
Hepatocyte ploidy is a diversity factor for liver homeostasis Front. Physiol. (8) 862, 2017.

P. Fisch, S. Rathmann, C. Keck, C. Kreutz, N. Weit, M. Mueller, J. Timmer, S. Glatzel, M. Follo, M. Malkovsky, J. Finke, R. Handgretinger, M. Werner.
Partial break in tolerance of NKG2A-/LIR-1- single KIR+ NK cells early in the course of HLA matched, KIR mismatched hematopoietic cell transplantation. Bone Marrow Transplantation , 2017, 52(8), 1144-1155.

O. Ucar, K. Li, D. Dvornikov, C. Kreutz, J. Timmer, S. Matt, L. Brenner, C. Smedley, M.A. Travis, T.G. Hofmann, U. Klingmueller B. Kyewski.
A thymic epithelial stem cell pool persists throughout ontogeny and is modulated by TGF-beta.
Cell Reports 17, 448-457, 2016.

C. Kreutz
New Concepts for Evaluating the Performance of Computational Methods.
IFAC-PapersOnLine (2016) 49(26): 63-70.

Tim Maiwald, H. Hass, B. Steiert, J. Vanlier, R. Engesser, A. Raue, F. Kipkeew, H. Bock, D. Kaschek, C. Kreutz, J. Timmer
Driving the Model to Its Limit: Profile Likelihood Based Model Reduction
PLoS ONE (2016) 11(9): e0162366. doi: 10.1371/journal.pone.0162366

H. Binder, T. Kurz, S. Teschner, C. Kreutz, M. Geyer, J. Donauer, A. Kraemer-Guth, J. Timmer, M. Schumacher and G. Walz
Dealing with prognostic signature instability: a strategy illustrated for cardiovascular events in patients with end-stage renal disease
BMC Medical Genomics (2016) 9(43), doi:10.1186/s12920-016-0210-9

B. Steiert, J. Timmer, C. Kreutz
L1 regularization facilitates detection of cell type-specific parameters in dynamical systems.
Bioinformatics (2016) 32(17): i718-i726 doi:10.1093/bioinformatics/btw461

R. Merkle, B. Steiert, F. Salopiata, S. Depner, A. Raue, N. Iwamoto, M. Schelker, H. Hass, M. Waesch, M. Boehm, O. Muecke, D. Lipka, C. Plass, W. Lehmann, C. Kreutz, J. Timmer, M. Schilling, U. Klingmueller
Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.
PLoS Comput Biol (2016) 12(8): e1005049. doi:10.1371/journal.pcbi.1005049

H. Hass, C. Kreutz J. Timmer and D. Kaschek
Fast integration-based prediction bands for ordinary differential equation models.
Bioinformatics (2016) 32 (8): 1204-1210, doi:10.1093/bioinformatics/btv743

C. Kreutz, A. Raue, J. Timmer
Statistics for Model Calibration
Multiple Shooting and Time Domain Decomposition Methods, Vol. 9 of the series Contributions in Mathematical and Computational Sciences, 2015, pp 355-375

L.O. Schwen, A. Schenk, C. Kreutz J. Timmer, M.M. Bartolome Rodriguez, L. Kuepfer, T. Preusser
Representative sinusoids for hepatic four-scale pharmacokinetics simulations.
Plos One (2015) 10, e0133653

A. Raue, B. Steiert, M. Schelker, C. Kreutz T. Maiwald, H. Hass, J. Vanlier, C. Toensing, L. Adlung, R. Engesser, W. Mader, T. Heinemann, J. Hasenauer, M. Schilling, T. Hoefer, E. Klipp, F. Theis, U. Klingmueller, B. Schoeberl, J. Timmer.
Data2Dynamics: a modeling environment tailored to parameter estimation in dynamical systems
Bioinformatics (2015) 31 (21): 3558-3560

J. Karr, A. Williams, J. Zucker, A. Raue, B. Steiert, J. Timmer, C. KreutzS. Wilkinson, B.Allgood, B. Bot, B. Hoff, M. Kellen, M. Covert, G. Stolovitzky, P. Meyer, DREAM8 Parameter Estimation Challenge Consortium
Summary of the DREAM8 Parameter Estimation Challenge: Toward Parameter Identification for Whole-Cell Models
Plos Comput Biol. (2015) 11(5), e1004096

Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher L, Basters A, Staszewski O, Brendecke SM, Spiess A, Tay TL C. Kreutz Timmer J, Mancini GM, Blank T, Fritz G, Biber K, Lang R, Malo D, Merkler D, Heikenwaelder M, Knobeloch KP, Prinz M
USP18 lack in microglia causes destructive interferonopathy of the mouse brain
The EMBO journal, 2015, e201490791

C. Toensing, J. Timmer, C. Kreutz
On the cause and cure of sloppiness in ordinary differential equation models
Phys. Rev. E (2014) 90, 023303
arXiv preprint version

S. Wahane, N. Hellbach, M. Prentzell, S. Weise, R. Vezzali, C. Kreutz, J. Timmer, K. Krieglstein, K. Thedieck, T. Vogel
PI3K-p110-alpha-subtype-signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2
JNC (2014) 130(2):255-267

K. Aumann, A.-V. Frey, A.M. May, D. Hauschke, C. Kreutz, J.P. Marx, J. Timmer, M. Werner, H.L. Pahl
Differenzialdiagnose myelproliferativer Neoplasien
Der Pathologe 34:201-209, DOI 10.1007/s00292-013-1824-8

Meyer, P.; Cokelaer, T.; Chandran, D.; Kim, K. H.; Loh, P.-R.; Tucker, G.; Lipson, M.; Berger, B.; Kreutz, C. Raue, A.; Steiert, B.; Timmer, J.; Bilal, E.; DREAM6 and DREAM7 Consortium; Sauro, H. M.; Stolovitzky, G. & Saez-Rodriguez, J.
Network topology and parameter estimation: from experimental design methods to gene regulatory network kinetics using a community based approach. BMC systems biology, 8(1), 1, 2014

Raue A, Schilling M, Bachmann J, Matteson A, Schelker M, Kaschek D, Hug S, Kreutz C, Harms BD, Theis F, Klingmueller U and Timmer J.
Lessons Learned from Quantitative Dynamical Modeling in Systems Biology.
PLOS ONE 8(9), e74335, 2013

Raue A, Kreutz C, Theis F and Timmer J.
Joining Forces of Bayesian and Frequentist Methodology: A Study for Inference in the Presence of Non-Identifiability.
Phil. Trans. Roy. Soc. A, 371, 20110544, 2013;

Kreutz C, Raue A, Kaschek D, and Timmer J.
Profile Likelihood in Systems Biology.
FEBS Journal, 2013;

A. Yalcin, C. Kreutz, D. Pfeifer, M. Abdelkarim, G. Klaus, J. Timmer, M. Luebbert, B. Hackanson
MeDIP coupled with a promoter tiling array as a platform to investigate global DNA methylation patterns in AML cells.
Leukemia Research 2012;

C. Kreutz, A. Raue, J. Timmer
Likelihood based observability analysis and confidence intervals for predictions of dynamic models.
BMC Systems Biology 2012; 6; doi:10.1186/1752-0509-6-120
arXiv preprint version 2011

Schelker M, Raue A, Timmer J and Kreutz C
Comprehensive estimation of input signals and dynamical parameters in biochemical reaction networks.
Bioinformatics, 28(18), i522-i528, 2012;

B. Steiert, A. Raue, J. Timmer, C. Kreutz
Experimental design for parameter estimation of gene regulatory networks.
PLoS ONE 2012; 7, e40052; doi:10.1371/journal.pone.0040052

K Sa Ferreira, C Kreutz, S. MacNelly, K Neubert, A Haber, M Bogyo, J Timmer, C Borner
Caspase-3 feeds back on caspase-8, Bid and XIAP in type I Fas signaling in primary mouse hepatocytes
Apoptosis 2012; 17(5), 503-515; doi: 10.1007/s10495-011-0691-0

Kreutz C, Gehring JS, Lang D, Reski R, Timmer J, Rensing SA
TSSi - An R package for transcription start site identification from 5' mRNA tag data
Bioinformatics 2012; doi: 10.1093/bioinformatics/bts189

Bachmann J, Raue A, Schilling M, Bohm ME, Kreutz C, Kaschek D, Busch H, Gretz N, Lehmann WD, Timmer J, Klingmueller U.
Division of labor by dual feedback regulators controls JAK2/STAT5 signaling over broad ligand range.
Mol Syst Biol., 2011, 7, 516.

Raue A, Kreutz C, Maiwald T, Klingmueller U, Timmer J.
Addressing Parameter Identifiability by Model-Based Experimentation
IET Systems Biology, 2011, 5(2), 120-130.

Zellmer S, Schmidt-Heck W, Bauer A, Meyer C, Lehmann T, Sparna T, Godoy P, Amin P, Schormann W, Bedawy E, Hammad S, Kern C, Kreutz C, Timmer J, Walz G, von Weizs\"acker F, Thürmann PA, Dooley S, Merfort I, Guthke R, Hengstler JG, Gebhardt R.
The transcription factors ETF, E2F and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes.
Hepatology , 2010, 52(6), 2127-2136.

Schilling M, Maiwald T, Hengl S, Winter D, Kreutz C, Kolch W, Lehmann WD, Timmer J, Klingmüller U
Theoretical and experimental analysis links isoform-specific ERK signalling to cell fate decisions.
Mol Syst Biol. 2009;5:334.

Raue A, Kreutz C, Maiwald T, Bachmann J, Schilling M, Klingmüller U, Timmer J.
Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood.
Bioinformatics. 2009 Aug 1;25(15):1923-9.

Bartholome K., Kreutz C., Timmer J.
Estimation of gene induction enables a relevance-based ranking of gene sets
J Comput Biol. 2009 Jul;16(7):959-67.

Kreutz C, Timmer J.
Systems biology: experimental design.
FEBS J. 2009 Feb;276(4):923-42

Rumberger B, Kreutz C, Nickel C, Klein M, Lagoutte S, Teschner S, Timmer J, Gerke P, Walz G, Donauer J.
Combination of immunosuppressive drugs leaves specific "fingerprint" on gene expression in vitro.
Immunopharmacol Immunotoxicol. 2009 Mar 9:1-10

Lassmann S, Kreutz C, Schoepflin A, Hopt U, Timmer J, Werner M.
A novel approach for reliable microarray analysis of microdissected tumor cells from formalin-fixed and paraffin-embedded colorectal cancer resection specimens.
J Mol Med
. 2009 Feb;87(2):211-24.

Maiwald, T; Kreutz, C; Pfeifer, AC; et al.
Dynamic pathway modeling - Feasibility analysis and optimal experimental design
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1115: 212-220 2007

Rumberger, B; Vonend, O; Kreutz, C; et al.
cDNA microarray analysis of adaptive changes after renal ablation in a sclerosis-resistant mouse strain
KIDNEY & BLOOD PRESSURE RESEARCH, 30 (6): 377-387 2007

Hengl, S; Kreutz, C; Timmer, J; et al.
Data-based identifiability analysis of non-linear dynamical models
BIOINFORMATICS, 23 (19): 2612-2618 OCT 1 2007

Kreutz, C; Rodriguez, MMB; Maiwald, T; et al.
An error model for protein quantification
BIOINFORMATICS, 23 (20): 2747-2753 OCT 15 2007

Lindenmeyer, MT; Kern, C; Sparna, T;  Donauer J, Wilpert J, Schwager J, Porath D, Kreutz C, Timmer J , Merfort I 
Microarray analysis reveals influence of the sesquiterpene lactone parthenolide on gene transcription profiles in human epithelial cells
LIFE SCIENCES, 80 (17): 1608-1618 APR 3 2007

Pfeifer, D; Pantic, M; Skatulla, I; Rawluk J, Kreutz C, Martens UM, Fisch P, Timmer J, Veelken H
Genome-wide analysis of DNA copy number changes and LOH in CLL using high-density SNP arrays
BLOOD, 109 (3): 1202-1210 FEB 1 2007

Klingmuller, U; Bauer, A; Bohl, S; Nickel PJ, Breitkopf K, Dooley S, Zellmer S, Kern C, Merfort I, Sparna T, Donauer J, Walz G, Geyer M, Kreutz C, Hermes M, Gotschel F, Hecht A, Walter D, Egger, Neubert K, Borner C, Brulport M, Schormann W, Sauer C, Baumann F, Preiss R, MacNelly S, Godoy P , Wiercinska E, Ciuclan L, Edelmann J, Zeilinger K, Heinrich M , Zanger UM, Gebhardt R, Maiwald T, Heinrich R, Timmer J, von Weizsacker F, Hengstler JG 
Primary mouse hepatocytes for systems biology approaches: a standardized in vitro system for modelling of signal transduction pathways
IEE PROCEEDINGS SYSTEMS BIOLOGY, 153 (6): 433-447 NOV 2006

Schieren, G; Rumberger, B; Klein, M; Kreutz C, Wilpert J, Geyer M, Faller D, Timmer J, Quack I, Rump LC, Walz G, Donauer J
Gene profiling of polycystic kidneys
NEPHROLOGY DIALYSIS TRANSPLANTATION, 21 (7): 1816-1824 JUL 2006

Fang, X; Zeisel,MB; Wilpert, J; Gissler B, Thimme R, Kreutz C, Maiwald T, Timmer J, Kern WV, Donauer J, Geyer M, Walz G, Depla E, von Weizsacker F, Blum HE, Baumert TF
Host cell responses induced by hepatitis C virus binding
HEPATOLOGY, 43 (6): 1326-1336 JUN 2006

Schilling, M; Maiwald, T; Bohl, S; Kollmann M, Kreutz C, Timmer J, Klingmuller U
Quantitative data generation for systems biology: the impact of randomisation, calibrators and normalisers
IEE PROCEEDINGS SYSTEMS BIOLOGY, 152 (4): 193-200 DEC 2005

Schilling, M; Maiwald, T; Bohl, S;  Kollmann M, Kreutz C, Timmer J, Klingmuller U
Computational processing and error reduction strategies for standardized quantitative data in biological networks
FEBS JOURNAL, 272 (24): 6400-6411 DEC 2005

Goerttler, PS; Kreutz, C; Donauer, J; et al.
Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2
BRITISH JOURNAL OF HAEMATOLOGY, 129 (1): 138-150 APR 2005

Fang, X; Wilpert, J; Barth, H; Gissler B, Kreutz C, Timmer J, Donauer J, von Weizsacker F, Blum HE, Baumert TF
Binding of hepatitis C virus envelope to target cells induces a cascade of cell signals important for antiviral immune responses and lipid metabolism.
HEPATOLOGY, 40 (4): 451A-451A Suppl. 1 OCT 2004

Goerttler, PS; Faller, D; Donauer, J; Klein M, Kreutz C, Maiwald T, Rumberger B, Sparna T, Timmer J, Wilpert J, Walz G, Pahl HL
cDNA microarray analysis of patients with polycythemia vera and secondary erythrocytosis.
BLOOD, 102 (11): 147A-147A 505 Part 1 NOV 16 2003

Kreutz, C; Honerkamp J.
Controlling the continuos positive airway pressure-device using partial observable Markov decision processes
MODELLING, SIMULATION AND OPTIMIZATION OF COMPLEX PROCESSES, 129 (1): 273-286, 2005.

Clemens Kreutz.
Statistical Approaches for Molecular and Systems Biology
PhD Thesis, University of Freiburg, 2012.

Clemens Kreutz.
Steuerung Stochastischer Systeme
Dipoma thesis, University of Freiburg, 2003.

 
Data
 
The data from the manuscript An error model for protein quantification
 
Software packages
 
A Matlab package tailored to efficient parameter estimation and model inference:
Data2Dynamics Software (D2D)

Bioconductor R-package for the estimation of the number of regulated genes in a gene set:
Gene Set Regulation Index (GSRI)

Bioconductor R-package for Identifying Regulation by Tiling Microarray Data:
Loci of Enhanced Significance (LES)

Bioconductor R-package for Transcription Start Site Prediciton (TSS):
Transcription Start Site Identification (TSSi)

 
Awards
 

Certificate for best performing in the DREAM6 parameter estimation challenge.
Certificate for best performing in the DREAM7 network inference challenge.
Certificate for best performing in the DREAM8 whole cell parameter inference challenge.

 

Selected Publications

1.           Kreutz, C. (2018). An easy and efficient approach for testing identifiability. Bioinformatics, 34(11), 1913-1921. doi:10.1093/bioinformatics/bty035

2.           Kreutz, C. (2016). New Concepts for Evaluating the Performance of Computational Methods., IFAC-PapersOnLine 49(26), 63-70. doi:10.1016/j.ifacol.2016.12.104

3.           Lucarelli, P., Schilling, M., Kreutz, C., Vlasov, A., Boehm, M. E., Iwamoto, N., . . . Klingmüller, U. (2018). Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression. Cell systems, 6(1), 75-89.e11. doi:10.1016/j.cels.2017.11.010

4.           Kreutz, C., MacNelly, S., Follo, M., Wäldin, A., Binninger-Lacour, P., Timmer, J., & Bartolomé-Rodríguez, M. M. (2017). Hepatocyte Ploidy Is a Diversity Factor for Liver Homeostasis. Frontiers in physiology, 8, 862. doi:10.3389/fphys.2017.00862

5.           Steiert, B., Timmer, J., & Kreutz, C. (2016). L1 regularization facilitates detection of cell type-specific parameters in dynamical systems. Bioinformatics, 32(17), i718-i726. doi:10.1093/bioinformatics/btw461

6.           Kreutz, C., Raue, A., Kaschek, D., & Timmer, J. (2013). Profile likelihood in systems biology. The FEBS journal, 280(11), 2564-2571. doi:10.1111/febs.12276

7.           Kreutz, C., Raue, A., & Timmer, J. (2012). Likelihood based observability analysis and confidence intervals for predictions of dynamic models. BMC systems biology, 6, 120. doi:10.1186/1752-0509-6-120

8.           Kreutz, C., & Timmer, J. (2009). Systems biology: experimental design. The FEBS journal, 276(4), 923-942. doi:10.1111/j.1742-4658.2008.06843.x

9.           Raue, A., Kreutz, C., Maiwald, T., Bachmann, J., Schilling, M., Klingmüller, U., & Timmer, J. (2009). Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood. Bioinformatics, 25(15), 1923-1929. doi:10.1093/bioinformatics/btp358

10.         Kreutz, C., Bartolome Rodriguez, M. M., Maiwald, T., Seidl, M., Blum, H. E., Mohr, L., & Timmer, J. (2007). An error model for protein quantification. Bioinformatics, 23(20), 2747-2753. doi:10.1093/bioinformatics/btm397

 

Publications

University of Freiburg Research Database:

[2019] [2018] [2017] [2016] [2015] [Older publications]

Short CV

Since 2019: Unit Head at the Institut für Medizinische Biometrie und Statistik (IMBI)

2016 - 2019: Head of Data Analysis & Algorithm Selection Group  at the Center for Biosystems Analysis (ZBSA), Habsburger Str. 49, University of Freiburg

2012 - 2016: PostDoc at the Physics Institute, Hermann-Herder Str. 3, University of Freiburg

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