Supervised and unsupervised analyses in next generation sequencing data:
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| Main Author: | |
|---|---|
| Format: | Thesis Book |
| Language: | English |
| Published: |
Heidelberg
[2018]
|
| Subjects: | |
| Online Access: | Inhaltsverzeichnis Inhaltsverzeichnis |
| Physical Description: | xxiv, 269 Seiten Illustrationen, Diagramme 30 cm |
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| 100 | 1 | |a Hübschmann, Daniel |d 1981- |e Verfasser |0 (DE-588)1099133653 |4 aut | |
| 245 | 1 | 0 | |a Supervised and unsupervised analyses in next generation sequencing data |c presented by Dr. med. Dipl. Phys. Daniel Huebschmann, CASM ; referees: Prof. Dr. Roland Eils, Prof. Dr. Karsten Rippe |
| 264 | 1 | |a Heidelberg |c [2018] | |
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| adam_text |
CONTENTS
LIST OF FIGURES XV
LIST OF TABLES XIX
LIST OF ABBREVIATIONS XXI
1 INTRODUCTION 1
1.1 NEXT GENERATION
SEQUENCING.
1
1.2 CANCER G E N O M IC S
.
2
1.3 PATTERN RE C O G N ITIO N
.
3
1.3.1 UNSUPERVISED PATTERN RECOGNITION: NON-NEGATIVE MATRIX
FACTORIZATION . . 3
1.3.2 SUPERVISED PATTERN RECO G N ITIO N
. 6
1.4 MUTATIONAL SIG N ATU
RES.
7
1.4.1 F RA M E W O RK
.
7
1.4.2 PUBLISHED MUTATIONAL S IG N A TU RE S
. 9
1.4.3 ALGORITHMIC IM
PLICATIONS.
14
1.5 HOMOLOGOUS RECOMBINATION REPAIR AND B R C A
NESS. 15
1.6 THE HEMATOPOETIC S Y STE M
.
17
1.7 GERMINAL CENTER DERIVED B-CELL LYMPHOMAS
. 19
1.7.1 BURKITT LYM PHOM AS
.
21
1.7.2 NON-BURKITT LY M P H O M A
S.
22
1.7.3 MUTATIONAL MECHANISMS
.
23
1.8 LEIOM YOSARCOM
AS.
23
1.9 C H O RD O M A S
.
24
1.10 RADIATION INDUCED M E N IN G IO M A
S.
24
1.11 PERSONALIZED O N C O LO G Y
.
25
1.12 AIM OF THE P RO JE C
T.
26
2 RESULTS 27
2.1 UNSUPERVISED PATTEM RECOGNITION: B RATW
URST. 27
2.1.1 GPU-BASED DECOMPOSITION OF HIGH-DIMENSIONAL D A TA S E TS
.
27
2.2 SUPERVISED PATTERN RECOGNITION: Y A P S A
.
37
2.2.1 USAGE OF Y A P S A
.
37
2.2.2 DETERMINATION OF SIGNATURE-SPECIFIC CUTOFFS VIA AN OPTIMIZATION
PROCE
DURE (ROC ANALYSIS WITH CUSTOM COST F U N C TIO N )
.
43
2.2.3 STRATIFIED ANALYSES OF MUTATIONAL S IG N A TU RE S
. 48
2.2.4 LIMITATIONS OF A BACK-ASSIGNMENT OF SIGNATURES TO S N V S
.
53
2.2.5 CONFIDENCE INTERVALS FOR THE EXPOSURE V ALU ES
.
54
2.2.6 ADDITIONAL CONSIDERATIONS ON THE PUBLISHED MUTATIONAL SIGNATURES
. 55
2.3 REGULATION OF TRANSCRIPTIONAL PROGRAMS IN H EM ATOPOESIS
.
59
2.3.1 LINKING SIGNATURES TO CELL TYPES
.
59
2.3.2 COMPARISON OF NMF AND PCA R E S U LTS
. 62
2.3.3 EXTRACTION OF SINGLE-SIGNATURE FE A TU RE S
. 65
2.3.4 COMPARISON OF THE SIGNATURES FROM RNA-SEQ AND A T A C -SEQ
.
65
2.3.5 DETAILED INTEGRATIVE ANALYSIS USING CHROMATIN CONFORMATION DATA
. 70
2.4 GERMINAL CENTER DERIVED B-CELL LYMPHOMAS
. 74
2.4.1 MUTATIONAL LAN D SCAP
E.
74
2.4.2 ABERRANT SHM AND ABERRANT CSR CAUSE CLUSTERS OF HYPERMUTATION . .
. 80
2.4.3 ENHANCERS ARE RECURRENTLY H YPERM UTATED
.
81
2.4.4 HYPERMUTATION BY PROXY AND IMPLICATIONS FOR THE GC R E A C TIO N
.
86
2.4.5 NEW MUTATIONAL SIGNATURES REFLECT MUTAGENIC MECHANISMS ACTIVE IN
GC
B CELLS
.
89
2.4.6 MUTATIONAL MECHANISMS DURING LYMPHOMA E V O LU TIO N
.
100
2.4.7 MAPPING BREAKPOINTS TO SWITCH REGIONS
. 102
2.5 BRCANESS IN LEIOMYOSARCOMAS
.
105
2.6 C H O RD O M A S
.
108
2.6.1 BRCANESS IN A CASE SERIES OF C H O RD O M A S
. 108
2.6.2 OFF-LABEL USE OF A PARP INHIBITOR IN ONE P A TIE N T
.
I L L
2.7 RADIATION INDUCED M E N IN G IO M A S
.
113
2.7.1 BRCANESS IN RADIATION INDUCED M ENINGIOM AS
.
113
2.7.2 DERIVATION OF A GROWTH MODEL FOR RADIATION INDUCED MENINGIOMAS . .
. 115
3 DISCUSSION 117
3.1 PATTERN RECOGNITION AND SOFTWARE D EV ELO P M EN
T. 117
3.1.1 UNSUPERVISED PATTERN RECOGNITION
.118
3.1.2 SUPERVISED PATTEM RECO G N ITIO N
.
123
3.2 H EM
ATOPOESIS.
129
3.3 B-CELL BIOLOGY AND
LYMPHOMAGENESIS.137
3.4 HOMOLOGOUS RECOMBINATION REPAIR AND B R C A
NESS. 147
3.5 MUTATIONAL PROCESSES IN CLONAL E V O LU TIO N
.152
4 METHODS 157
4.1 METHODS FOR UNSUPERVISED PATTEM RE C O G N ITIO N
.
157
4.1.1 A NEW NMF SOLVER FOR GPU C O M P U TIN G
. 157
4.1.2 QUALITY CRITERIA FOR THE DETERMINATION OF THE OPTIMAL
FACTORIZATION RANK . 158
4.1.3 THE BRATWURST W O RK FLO W
.159
4.2 METHODS FOR SUPERVISED PATTERN RECOGNITION
.
164
4.2.1 COMPUTING SIGNATURE EXPOSURES BY NON-NEGATIVE LEAST S Q U A R E S
.
164
4.2.2 DETERMINATION OF THE OPTIMAL C U TO FFS
.
164
4.2.3 DETERMINATION OF CONFIDENCE INTERVALS FOR THE EXPOSURES
.
165
4.2.4 ENRICHMENTS OF SIGNATURES EXPOSURES COMPARED TO A BACKGROUND OF
CAN
CER SAMPLES
.
165
4.2.5 STRATIFICATION OF THE MUTATIONAL CATA LO G
. 166
4.3 METHODS FOR THE UNSUPERVISED ANALYSIS OF HEM
ATOPOESIS.168
4.4 METHODS FOR NGS ANALYSIS IN THE ONCOLOGICAL P RO JE C TS
.
170
4.4.1 PATIENT SA M P LE
S.170
4.4.2 SAMPLE PROCESSING, ISOLATION OF AN ALY
TES.170
4.4.3 NEXT GENERATION SEQUENCING DATA
PROCESSING.171
4.4.4 DETECTION OF SNVS AND SMALL IN D E L S
.
171
4.4.5 EXTRACTION OF CLUSTERS OF SNVS AT HIGH AND INTERMEDIATE MUTATION
DENSITY 172
4.4.6 ANALYSIS OF MUTATIONAL S IG N A TU RE S
.
173
4.4.7 DETECTION OF GENOMIC STRUCTURAL REARRANGEM
ENTS.174
4.4.8 IDENTIFICATION OF COPY NUMBER ABERRATIONS AND ESTIMATION OF TUMOR
PLOIDY
AND TUMOR CELL C O N T E N T
.175
4.4.9 CALCULATION OF CELLULAR F R A C TIO N S
.175
4.4.10 HOMOLOGOUS RECOMBINATION DEFICIENCY AND LARGE-SCALE STATE
TRANSITION
S C O R E S
.
176
4.4.11 REPLICATION T I M I N G
.
176
4.5 ADDITIONAL METHODS FOR GERMINAL CENTER DERIVED B CELL LY M P H O M A
S
.
178
4.5.1 TRANSCRIPTOME A N A LY
SIS.178
4.5.2 IDENTIFICATION OF HALLMARK E V E N TS
.
178
4.5.3 PATIENT SA M P LE S
.
178
4.5.4 GENE EXPRESSION BASED GCBCL CLASSIFICATION
.179
4.5.5 CHROMATIN STATES FOR GC B C E L L S
.
179
4.5.6 WHOLE GENOME SEQUENCING DATA P RO C E S S IN G
.180
4.5.7 DETERMINATION OF IG SWITCH RE G I O N S
.180
4.5.8 CLASSIFICATION OF HYPERMUTATION CLUSTERS INTO SHM-LIKE AND
CSR-LIKE . 182
4.5.9 HYPERMUTATION BY P R O X Y
.
182
4.5.10 SYNTHETIC SHM SIG N ATU
RE.
183
4.6 ADDITIONAL METHODS FOR LE IO M Y O SA RC O M A
S. 184
4.6.1 CALLING OF SMALL VARIANTS IN CELL LIN E S
.184
4.6.2 CLONOGENIC A S S A Y S
.
184
4.7 ADDITIONAL METHODS FOR C H O RD O M A
S.
184
4.8 ADDITIONAL METHODS FOR LOW-DOSE RADIATION INDUCED M ENINGIOM
AS.185
5 CONCLUSIONS 189
6 OUTLOOK 193
7 OWN PUBLICATIONS 197
BIBLIOGRAPHY 205
APPENDIX A APPENDIX METHODS 237
APPENDIX B APPENDIX RESULTS
241 |
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| indexdate | 2025-01-24T11:02:16Z |
| institution | BVB |
| institution_GND | (DE-588)2024349-2 |
| language | English |
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| spelling | Hübschmann, Daniel 1981- Verfasser (DE-588)1099133653 aut Supervised and unsupervised analyses in next generation sequencing data presented by Dr. med. Dipl. Phys. Daniel Huebschmann, CASM ; referees: Prof. Dr. Roland Eils, Prof. Dr. Karsten Rippe Heidelberg [2018] xxiv, 269 Seiten Illustrationen, Diagramme 30 cm txt rdacontent n rdamedia nc rdacarrier Dissertation Ruperto-Carola University of Heidelberg 2018 Mit einer Zusammenfassung in englischer und deutscher Sprache (DE-588)4113937-9 Hochschulschrift gnd-content Eils, Roland 1965- (DE-588)1020648287 dgs Universität Heidelberg (DE-588)2024349-2 dgg B:DE-101 application/pdf http://d-nb.info/1164263803/04 Inhaltsverzeichnis DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030614399&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Hübschmann, Daniel 1981- Supervised and unsupervised analyses in next generation sequencing data |
| subject_GND | (DE-588)4113937-9 |
| title | Supervised and unsupervised analyses in next generation sequencing data |
| title_auth | Supervised and unsupervised analyses in next generation sequencing data |
| title_exact_search | Supervised and unsupervised analyses in next generation sequencing data |
| title_full | Supervised and unsupervised analyses in next generation sequencing data presented by Dr. med. Dipl. Phys. Daniel Huebschmann, CASM ; referees: Prof. Dr. Roland Eils, Prof. Dr. Karsten Rippe |
| title_fullStr | Supervised and unsupervised analyses in next generation sequencing data presented by Dr. med. Dipl. Phys. Daniel Huebschmann, CASM ; referees: Prof. Dr. Roland Eils, Prof. Dr. Karsten Rippe |
| title_full_unstemmed | Supervised and unsupervised analyses in next generation sequencing data presented by Dr. med. Dipl. Phys. Daniel Huebschmann, CASM ; referees: Prof. Dr. Roland Eils, Prof. Dr. Karsten Rippe |
| title_short | Supervised and unsupervised analyses in next generation sequencing data |
| title_sort | supervised and unsupervised analyses in next generation sequencing data |
| topic_facet | Hochschulschrift |
| url | http://d-nb.info/1164263803/04 http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=030614399&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT hubschmanndaniel supervisedandunsupervisedanalysesinnextgenerationsequencingdata AT eilsroland supervisedandunsupervisedanalysesinnextgenerationsequencingdata AT universitatheidelberg supervisedandunsupervisedanalysesinnextgenerationsequencingdata |
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