UiO-UCSD Proposal. Hovig-Dale: Understanding DNA variants

A. Project Scope (1) The relevance of the scientific problem within the biological and medical sciences: Most common human disorders are now regarded as complex diseases, with a large number of DNA variants each contributing to the phenotype with a small effect. A large number of Single Nucleotide Polymorphisms (SNPs) have been identified from large genome-wide association studies (GWAS) in various disease contexts. We have developed novel statistical tools to improve discovery of these associations[1]. Despite the success of GWAS, only few of the identified SNPs have direct bearing on the protein coding sequence in the local sequence context, as the majority occurs in noncoding DNA. These variants are mostly indirectly associated with disease, associating a region of DNA with the phenotype. The steps from this rather vague association to functional association of phenotype with genotype is generally very demanding, as there may be many relationships that do not necessarily fall close to the variant identified by the GWAS. A case in point is that of a variant identified for contributing to obesity, originally reported to be associated to the closely located gene FTO. However, it was recently found that the variant rather was influencing a transcription factor, IRX3, located megabases away from the tag SNP variant, through chromatin loop formation. There is a lack of strongly predictive methods to address the relationship between noncoding DNA variants and regulatory mechanisms in noncoding DNA.

(2) Computational approaches to be used to address this problem, extending prior work in this field We have unique possibilities to address this field, as we have developed 1) a generic system for statistical genomics, termed the Genomic HyperBrowser [2-6] that is perfectly suited to approach a quantitative understanding of relevant features, relying on existing high-throughput and functional data, and 2) novel Bayesian statistical tools to improve discovery of common variants building on enrichment due to gene annotation [1] and pleiotropy [7,8] for a range of disorders [8-10]. Together, we will build a powerful toolbox, including a set of existing and novel statistical tests, to address questions on biological features along the genome, both in global and regional contexts, as well as three-dimensional settings. Combined with the rich sources of public data on chromatin information from such sources as ENCODE, Roadmap Epigenomics, FANTOM5, The Cancer Genome Atlas, Gene Expression Omnibus and others, and with knowledge sources from the biomedical literature, this opens for a completely novel level of integrated power of analysis. We recently developed functionality for direct import of data from the above mentioned data sources into our HyperBrowser package, and are thus able to take on the challenge. Using this system, we will utilize information on chromatin activation in all relevant tissues for a given phenotype, together with information on transcription status of all relevant promoters, as well as transcription information and where available also 3D information, in order to home in on candidate functional mechanisms. These will be prioritized by applying our novel enrichment toolbox, leveraging information from the huge international GWAS data sets available to the team. The approach will give a completely novel level of integrated power of analysis, permitting multi-scale analysis from the base-pair level, up to chromatin loops and beyond. We will primarily concentrate on the phenotypes of psychiatric disease and heritable cancer, as we have specific domain competence within these areas.

B. Inter-Institutional Collaboration (1) This project will be based primarily at UiO It will include one year stay at UCSD, in addition to regular visits between the two sites (2) The contributing faculty at UiO, and their roles Eivind Hovig, Dept of Informatics, primary advisor Geir Kjetil Sandve, Dept of Informatics, secondary advisor, Ole A. Andreassen, Medical Faculty, secondary advisor, (3) The contributing faculty at UCSD, and their roles Anders M. Dale, primary advisor,

1 Dominic Holland, secondary advisor (4) Fostering of collaboration between the UCSD and Oslo groups, and distribution of the major scientific and training objectives of the proposal between Oslo and San Diego The project will provide a major advantage in computational and statistical genetics, bringing together the functional genomics analytical expertise in Oslo, and the statistical genomics expertise in San Diego. It will serve to disseminate knowledge on genomic scale functional analysis to San Diego, and will forge strategic links that have been loosely established between Dept of Informatics and UC San Diego. It will further strengthen cross faculty collaboration in Oslo, linking the project to existing collaborations between Ole A Andreassen and Anders M. Dale.

C. International and Local Training (1) Courses to be taken at UiO MNSES9100 - Science, Ethics and Society STK9030 - Modern data analysis STK9021 - Applied Bayesian Analysis and Numerical Methods INF9825 - Algorithms for artificial intelligence and natural language processing (2) Additional professional/research training activities at UiO The candidate will be enrolled in The Genomic HyperBrowser scientific team, consisting of several faculty participants, 3-4 researcher/postdocs, and a similar number of PhD students, and as such be participating in transdisciplinary activities within this platform. (3) Additional professional/research training activities at UCSD Statistical genetics, Bayesian statistics, software tools, survival analysis (4) Advisor monitoring of student’s progress and development This will be achieved in regular supervisory group meetings at each institution on a biweekly basis, with inter-institutional participation by web based teleconferencing bimonthly or more.

References: 1. Schork AJ, Thompson WK, Pham P, Torkamani A, Roddey JC, et al. (2013) PLoS Genet 9: e1003449. 2. Sandve GK, Gundersen S, Rydbeck H, Glad IK, Holden L, et al. (2010) Genome Biol 11: R121. 3. Sandve GK, Gundersen S, Rydbeck H, Glad IK, Holden L, et al. (2011) BMC Genomics 12: 353. 4. Sandve GK, Gundersen S, Johansen M, Glad IK, Gunathasan K, et al. (2013) Nucleic Acids Res 41: W133-141. 5. Paulsen J, Sandve GK, Gundersen S, Lien TG, Trengereid K, et al. (2014) Bioinformatics 30: 1620-1622. 6. Paulsen J, Lien TG, Sandve GK, Holden L, Borgan O, et al. (2013) Nucleic Acids Res 41: 5164- 5174. 7. Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, et al. (2013) Nat Genet 45: 670-675. 8. Andreassen OA, Djurovic S, Thompson WK, Schork AJ, Kendler KS, et al. (2013) Am J Hum Genet 92: 197-209. 9. Andreassen OA, McEvoy LK, Thompson WK, Wang Y, Reppe S, et al. (2014) Hypertension 63: 819-826. 10. Andreassen OA, Harbo HF, Wang Y, Thompson WK, Schork AJ, et al. (2015) Mol Psychiatry 20: 207-214.

2 Eivind Hovig – Curriculum vitae Gender: Male Year of birth: 1953 Nationality: Norwegian E-mail: [email protected]

Oslo University Hospital/ Institute of Cancer Research/Section of Tumour Biology and /Institute of Informatics/ Biomedical informatics group Academic degree: Candidatus realium, 1983, Department of General Genetics, University of Oslo, Doctor philos., 1992, Medical Faculty, University of Oslo. Research experience 1980-91: Student and pre-doctoral work at The Norwegian Radium Hospital, Institute for Cancer Research, Department of Genetics. 1992-96: Post-doctoral research fellow at The Norwegian Radium Hospital, Institute for Cancer Research, Department of Tumor Biology. 1997-: Research fellow, group leader at The Norwegian Radium Hospital, Institute for Cancer Research, the Department of Tumor Biology 2005- : Section head, Medical Informatics, Radium-Rikshospitalet 2005- : Adjunct professor, Institute for Informatics, University of Oslo. Awards 2001: Dr. Ragnar Mørks award for scientifc excellence 2002: Diploma SND Inventor prize Publication statistics ISI: Hirsch-index: 34. Sum of the times cited: 5403, citing articles: 4821, average citations per item: 27.6 Scopus profle: http://tinyurl.com/pdc2qtb, Google Scholar profle (http://tinyurl.com/8up5ck9):

All Since 2010 Citations 7324 2127 h-index 40 25 i10-index 92 60 i10-index is the number of articles with at least 10 citations Patents: 6 international patents International funding Partner in two EU projects: (ComplexDis, Framework 6), MultiMod (Framework 7), collaborator in NCI project: Prediagnostic allergy and immune-related biomarkers in glioma risk and survival. J. Schwartzbaum PI). Teaching experience Supervision of twelve doctoral students, two diploma engineers, two medical students, and one agricultural student. Presently supervising fve doctoral students, and co- supervising two other doctoral students. Current group leader for two research groups: Genomics and melanoma: 7 members. The group centers on systems biology approaches for melanoma, combining in silico and wet lab work to develop regulatory models of central oncogenic pathways, the master switch of melanoma (MITF), and oncogene induced senescence. Bioinformatics: 6 members. The group has pioneered the concepts of network models with high throughput genomics and DNA denaturation genomics. Currently, the group continues to develop statistical approaches for genomic information, including support for chromatin 3D datasets, solutions for personalized medicine and novel systems biology approaches. Administrative experience:

1 Member of the steering group of the national FUGE boinformatics platform 2002-2012, and member of the steering group of the national genotyping network. Head of Oslo Elixir Node (European Bioinformatics infrastructure). Head of two OUS/UiO facilities: Bioinformatics for the last fve years (and of Genotyping closing by start 2015). Board member and key scientist in the Center for Research-based innovation: Statistics for innovation (Research council of ). (2007-2014), and partner of SFI Big insight - Statistics for the knowledge economy (2015-2022). Currently serving as member of the consulting group of the UiO project for secure computing (TSD2.0), member of the executive group of StoreBioInfo (a sustainable data storage solution for the Norwegian life sciences, in collaboration with UiB and Uninett Sigma), member of the steering group of Aqua Genome Project (CEES), core member of the National Cancer Genomics Consortium (NCGC) and supervising MetAction bioinformatics. The latter two projects have been funded through the RCN Biotek2021 program. Reviewer for science councils of EU (Marie Curie), BBRC (UK), Quatar, , Faeroe islands and Wallenberg Foundation and SciLife, Sweden. Organizer of SocBin2014 (Northern European bioinformatics conference). Editorial activities: Associate editor: BMC Bioinformatics (2007-present), editorial board member: BMC Genomics (2006-present); International Journal of Genomics (2009-present); Tidsskriftet Materialisten (crossdisciplinary peer-reviewed journal, 1984-present). Referee in around 50 different journals, including Nature Genetics, Human Genetics, Bioinformatics and Nucl Acids Res. Scientifc committee member of Biocreative II.5 (http://tinyurl.com/8g5c9rw) and BioCreative III (http://tinyurl.com/9c8g4sx), which is a community based effort for “Critical Assessment of Information Extraction in Biology”. Industry contacts: Scientifc consultant to Biomolex AS. This company is based on the patent application of Hovig, Skretting et al. above. Cofounder and shareholder in the Norwegian based bioinformatics company, PubGene Inc., based on a patent of Hovig, Jenssen et al. (US8886522 B2), board member of the company GeneSeque AS, Trondheim and board member and shareholder of the recently formed company OncoImmunity AS. Publications by Eivind Hovig (2010-15)

152 in print (of which 136 original articles, 8 review articles, 7 other articles, 1 book, 1 book chapter and 2 theses).

Original articles:

138. Christiansen IK, Sandve GK, Schmitz M, Dürst M, Hovig E (2015) Transcriptionally Active Regions Are the Preferred Targets for Chromosomal HPV Integration in Cervical Carcinogenesis PLoS One, 10 (3), e0119566 PubMed25793388 137. Rustad EH, Dai HY, Hov H, Coward E, Beisvag V, Myklebost O, Hovig E, Nakken S, Vodák D, Meza-Zepeda LA, Sandvik AK, Wader KF, Misund K, Sundan A, Aarset H, Waage A (2015) BRAF V600E mutation in early-stage multiple myeloma: good response to broad acting drugs and no relation to prognosis Blood Cancer J, 5, e299 PubMed 25794135 136. Lau C, Nygård S, Fure H, Olstad OK, Holden M, Lappegård KT, Brekke OL, Espevik T, Hovig E, Mollnes TE (2015) CD14 and Complement Crosstalk and Largely Mediate the Transcriptional Response to Escherichia coli in Human Whole Blood as Revealed by DNA Microarray PLoS One, 10 (2), e0117261 PubMed 25706641 135. Wibom C, Späth F, Dahlin AM, Langseth H, Hovig E, Rajaraman P, Børge Johannesen T, Andersson U, Melin B (2015) Investigation of established genetic risk variants for glioma in pre-diagnostic samples from a population based nested case control study Cancer Epidemiol Biomarkers Prev (in press) PubMed 25713050 134. Clancy T, Hovig E (2014) Differential protein network analysis of the immune cell lineage Biomed Res Int, 2014, 363408 PubMed25309909

2 133. Paulsen J, Rødland EA, Holden L, Holden M, Hovig E (2014) A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions Nucleic Acids Res, 42 (18), e143 PubMed25114054 132. Chilamakuri CS, Lorenz S, Madoui MA, Vodák D, Sun J, Hovig E, Myklebost O, Meza-Zepeda LA (2014) Performance comparison of four exome capture systems for deep sequencing BMC Genomics, 15, 449 PubMed24912484 131. Thingnes J, Øyehaug L, Hovig E. (2014) Mathematics and biological process of skin pigmentation. In Computational Biophysics of the Skin. Querleux B (ed.) Pan Stanford Publishing Pte Ltd. ISBN 978-981- 4463- 84- 3 (Hardcover) ISBN 978- 981- 4463-85- 0 (eBook) 130. Nygård S, Reitan T, Clancy T, Nygaard V, Bjørnstad J, Skrbic B, Tønnessen T, Christensen G, Hovig E. Identifying pathogenic processes by integrating microarray data with prior knowledge. BMC Bioinformatics, 15 (1), 115. 129. Nygaard V, Prasmickaite L, Vasiliauskaite K, Clancy T, Hovig E. Melanoma brain colonization involves the emergence of a brain-adaptive phenotype. (2014) OncoScience 1(1):82-94. 128. Paulsen J, Sandve GK, Gundersen S, Lien TG, Trengereid K, Hovig E (2014). HiBrowse: multi-purpose statistical analysis of genome-wide chromatin 3D organization Bioinformatics, 30 (11), 1620-2. 127. Sandve GK, Nekrutenko A, Taylor J, Hovig E. Ten simple rules for reproducible computational research. PLoS Comput Biol. 2013 Oct;9(10):e1003285. 126. Fromm B, Worren MM, Hahn C, Hovig E, Bachmann L. Substantial Loss of Conserved and Gain of Novel MicroRNA Families in Flatworms. Mol Biol Evol 30 (12), 2619-28. 125. Sandve GK, Nekrutenko A, Taylor J, Hovig E (2013). Ten simple rules for reproducible computational research PLoS Comput Biol, 9 (10), e1003285. 124. Bøe SL, Hovig E (2013). Enhancing nucleic acid delivery by photochemical internalization Ther Deliv, 4 (9), 1125-40 . 123. Schee K, Lorenz S, Worren MM, Günther CC, Holden M, Hovig E, Fodstad O, Meza-Zepeda LA, Flatmark K. Deep Sequencing the MicroRNA Transcriptome in Colorectal Cancer. PLoS One. 2013 Jun 18;8(6):e66165. 122. Sandve GK, Gundersen S, Johansen M, Glad IK, Gunathasan K, Holden L, Holden M, Liestøl K, Nygård S, Nygaard V, Paulsen J, Rydbeck H, Trengereid K, Clancy T, Drabløs F, Ferkingstad E, Kalas M, Lien T, Rye MB, Frigessi A, Hovig E. The Genomic HyperBrowser: an analysis web server for genome- scale data. Nucleic Acids Res. 2013 Jul;41(:W133-41. 121. Paulsen J, Lien TG, Sandve GK, Holden L, Borgan O, Glad IK, Hovig E. Nucleic Acids Res. 2013 May Handling realistic assumptions in hypothesis testing of 3D co-localization of genomic elements.1;41(10):5164-74. 120. Bøe SL, Jørgensen JA, Longva AS, Lavelle T, Sæbøe-Larssen S, Hovig E . Light- Controlled Modulation of Gene Expression Using Polyamidoamine Formulations Nucleic Acid Ther (in press) PubMed 23530684 119. Clancy T, Rodland EA, Nygard S, Hovig E . Predicting physical interactions between protein complexes Mol Cell Proteomics (in press) PubMed 23438732 118. Jørgensen JA, Longva AS, Hovig E, Bøe SL . Evaluation of Biodegradable Peptide Carriers for Light-Directed Targeting Nucleic Acid Ther PubMed 23405950 117. Mattingsdal M, Brown AA, Djurovic S, Sønderby IE, Server A, Melle I, Agartz I, Hovig E, Jensen J, Andreassen OA (2013) . Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways . Neuroimage, 70, 143-9 PubMed 23274185 116. Bøe SL, Hovig E (2013) Light-induced mRNA transfection. Methods Mol Biol, 969, 89-100 PubMed 23296929 115. Nakken S, Johansen M, Fillebeen J, Berge OP, Kirkerød H, Jenssen TK, Hovig E (2012) CellLineMiner: a knowledge portal for human cell lines . Bioinformation, 8 (22), 1119-22 PubMed 23251048 114. Skotheim RI, Meza-Zepeda LA, Hovig E, Lønning PE, Lothe RA, Myklebost O (2012) [Genome sequencing for personalized cancer treatment] Tidsskr Nor Laegeforen, 132 (21), 2406-8 PubMed 23160594

3 113. Kresse SH, Rydbeck H, Skårn M, Namløs HM, Barragan-Polania AH, Cleton- Jansen AM, Serra M, Liestøl K, Hogendoorn PC, Hovig E, Myklebost O, Meza- Zepeda LA (2012) Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma . PLoS One, 7 (11), e48262 PubMed 23144859 112.Thingnes J, Lavelle TJ, Hovig E, Omholt SW (2012) Understanding the melanocyte distribution in human epidermis: an agent-based computational model approach PLoS One, 7 (7), e40377 PubMed 22792296 111.Jørgensen JA, Hovig E, Bøe SL (2012) . Potent gene silencing in vitro at physiological pH using chitosan polymers Nucleic Acid Ther, 22 (2), 96-102 . 110.Thingnes J, Lavelle TJ, Gjuvsland AB, Omholt SW, Hovig E (2012) .Towards a quantitative understanding of the MITF-PIAS3-STAT3 connection . BMC Syst Biol, 6, 11 PubMed 22316093 109.Trachtenberg AJ, Robert JH, Abdalla AE, Fraser A, He SY, Lacy JN, Rivas- Morello C, Truong A, Hardiman G, Ohno-Machado L, Liu F, Hovig E, Kuo WP (2012) A primer on the current state of microarray technologies Methods Mol Biol, 802, 3-17 PubMed22130870 108.Bruhn S, Barrenäs F, Mobini R, Andersson BA, Chavali S, Egan BS, Hovig E, Sandve GK, Langston MA, Rogers G, Wang H, Benson M (2012) Increased expression of IRF4 and ETS1 in CD4+ cells from patients with intermittent allergic rhinitis Allergy, 67 (1), 33-40 PubMed 21919915 107.Liu F, Kuo WP, Jenssen TK, Hovig E (2012) Performance comparison of multiple microarray platforms for gene expression profling Methods Mol Biol, 802, 141-55 PubMed 22130879 106.Ågesen TH, Berg M, Clancy T, Thiis-Evensen E, Cekaite L, Lind GE, Nesland JM, Bakka A, Mala T, Hauss HJ, Fetveit T, Vatn MH, Hovig E, Nesbakken A, Lothe RA, Skotheim RI (2011) CLC and IFNAR1 are differentially expressed and a global immunity score is distinct between early- and late-onset colorectal cancer Genes Immun, 12 (8), 653-62 PubMed 21716316 105.Gundersen S, Kalaš M, Abul O, Frigessi A, Hovig E, Sandve GK (2011) Identifying elemental genomic track types and representing them uniformly BMC Bioinformatics, 12, 494 PubMed 22208806 104.Hjortland GO, Meza-Zepeda LA, Beiske K, Ree AH, Tveito S, Hoifodt H, Bohler PJ, Hole KH, Myklebost O, Fodstad O, Smeland S, Hovig E (2011) Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma BMC Cancer, 11, 455 PubMed 22014070 103.Bøe SL, Longva AS, Hovig E (2011) A novel photosensitizer for light- controlled gene silencing Nucleic Acid Ther, 21 (5), 359-67 PubMed 22004417 102.Bøe S, Prasmickaite L, Engesæter B, Hovig E (2011) Light-directed delivery of nucleic acids Methods Mol Biol, 764, 107-21 PubMed 21748636 101.Sandve GK, Gundersen S, Rydbeck H, Glad IK, Holden L, Holden M, Liestøl K, Clancy T, Drabløs F, Ferkingstad E, Johansen M, Nygaard V, Tøstesen E, Frigessi A, Hovig E (2011) The differential disease regulome BMC Genomics, 12, 353 PubMed 21736759 100.Clancy T, Pedicini M, Castiglione F, Santoni D, Nygaard V, Lavelle TJ, Benson M, Hovig E (2011) Immunological network signatures of cancer progression and survival BMC Med Genomics, 4, 28 PubMed 21453479 99. De Beule J, Hovig E, Benson M (2011) Introducing Dynamics into the Field of Biosemiotics A Formal Account with Examples from Language and Immunology Biosemiotics, 4 (1), 5-24

4 BIOGRAPHICAL SKETCH

NAME POSITION TITLE Dale, Anders Martin Professor of Neurosciences and Radiology, UCSD

eRA COMMONS USER NAME (credential, e.g., agency login) amdale

EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.) DEGREE INSTITUTION AND LOCATION (if applicable) MM/YY FIELD OF STUDY University of Texas, Austin, TX BA 06/85 Computer Science Harvard University, Cambridge, MA MS 05/91 Engineering University of California, San Diego PhD 12/94 Cognitive Science A. Personal Statement A major goal of my research program is to develop and apply advanced new methods for acquisition and analysis of multimodal neuroimaging data. Several of these methods have had major, and in some cases transformative, impact on their respective fields. Specific examples include 1) development of rapid event related experimental design and statistical analysis methods for fMRI, which have become a standard in the field of functional neuroimaging; 2) development of fully automated methods for segmentation of the cortical surface, subcortical nuclei, and white matter tracts from MRI scans – instantiated in the FreeSurfer software package, used by more than 10,000 researchers around the world; 3) development of standardized image acquisition protocols and analysis procedures enabling use of quantitative imaging biomarker in large-scale, multisite research studies, as well as in clinical practice – these procedures were fundamental to the success of the Alzheimer’s Disease Neuroimaging Initiative; 4) integration of structural and functional neuroimaging data within a Bayesian modeling framework, incorporating quantitative biophysical and physiological constraints and relationships. Another major goal of my research program is to characterize the genetic basis of variations in human complex traits and disorders. The initial focus has been on investigating genetic influences on structural and functional imaging biomarkers, combining twin designs and analysis with genetic association methods. An important result has been the development of methods for modeling quantifying pleotropic effects across phenotypic measures, which led to the first genetically based parcellation of the human cortex. The methods proposed in this grant naturally builds on these technologies developed in my lab, with applications that are likely to have transformative impact in a number of areas of fundamental importance to basic and clinical science. I am an author on more than 300 peer-reviewed publications, with more than 45,000 total citations, and an h-index of 94.

B. Positions and Honors Positions and Employment 1985-1987 Research Scientist, Norwegian Defense Research Establishment 1986 Visiting Scientist, European Center for Nuclear Research (CERN) 1996-1999 Instructor in Radiology, Harvard , Boston, MA 1999-2001 Assistant Professor in Radiology, Harvard Medical School, Boston, MA 1999-2004 Associate Director, Massachusetts General Hospital-Nuclear Magnetic Resonance Center 2001-2004 Associate Professor in Radiology, Harvard Medical School, Boston, MA 2004- Professor of Neurosciences, Radiology, Psychiatry, and Cognitive Science, UCSD 2004- Co-Director, Multimodal Imaging Laboratory, UCSD 2005- Director, Radiology Imaging Laboratory MRI Facility, UCSD 2010- Vice Chair for Research, Dept. of Radiology, UCSD 2013- Director, Center for Translational Imaging and Personalized Medicine, UCSD Honors 1988-1989 Fulbright Fellow, Harvard University, Cambridge, MA 1998 Wiley Young Investigator Award for Human Brain Mapping 1999-2002 Council Member, Secretary, Organization for Human Brain Mapping 2011- Member, Society for Neuroscience “One Mind for Research” Planning Committee

C. Selected Peer-reviewed Publications (from total of 300+) 1. Sereno MI, Dale AM, Reppas JB, Kwong KK, Belliveau JW, Brady TJ, Rosen BR, Tootell RB. Borders of multiple visual areas in humans revealed by functional magnetic resonance imaging. Science 1995;268(5212):889-893. PubMed PMID: 7754376. (1676 Citations) 2. Dale AM. Optimal experimental design for event-related fMRI. Hum Brain Mapp. 1999;8(2-3):109-14. PubMed PMID: 10524601. (893 Citations) 3. Dale AM, Fischl B, Sereno MI. Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 1999;9(2):179-194. PMID:9931269. (2306 Citations) 4. Dale AM, Liu AK, Fischl BR, Buckner RL, Belliveau JW, Lewine JD, Halgren E. Dynamic statistical parametric mapping: combining fMRI and MEG for high-resolution imaging of cortical activity. Neuron 2000;26(1):55-67. PMID:10798392. (746 Citations) 5. Fischl B, Salat DH, Busa E, Albert M, Dieterich M, Haselgrove C, van der Kouwe A, Killiany R, Kennedy D, Klaveness S, Montillo A, Makris N, Rosen B, Dale AM. Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain. Neuron. 2002 Jan 31;33(3):341-55. PubMed PMID: 11832223. (1534 Citations) 6. Bakken TE, Roddey JC, Djurovic S, Akshoomoff N, Amaral DG, Bloss CS, Casey BJ, Chang L, Ernst TM, Gruen JR, Jernigan TL, Kaufmann WE, Kenet T, Kennedy DN, Kuperman JM, Murray SS, Sowell ER, Rimol LM, Mattingsdal M, Melle I, Agartz I, Andreassen OA, Schork NJ, Dale AM; Alzheimer's Disease Neuroimaging Initiative; Pediatric Imaging, Neurocognition, and Genetics Study. Association of common genetic variants in GPCPD1 with scaling of visual cortical surface area in humans. Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3985-90. PubMed PMID: 22343285; PubMed Central PMCID: PMC3309762. 7. Desikan RS, McEvoy LK, Thompson WK, Holland D, Brewer JB, Aisen PS, Sperling RA, Dale AM; for the Alzheimer's Disease Neuroimaging Initiative. Amyloid-β-Associated Clinical Decline Occurs Only in the Presence of Elevated P-tau. Arch Neurol. 2012 Jun;69(6):709-13. PubMed PMID: 22529247; PubMed Central PMCID: PMC3423526. 8. Stein JL, et al. Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics. 2012 Apr 15;44(5):552-561. PubMed PMID: 22504417; PubMed Central PMCID: PMC3635491. 9. Chen CH, Gutierrez ED, Thompson W, Panizzon MS, Jernigan TL, Eyler LT, Fennema-Notestine C, Jak AJ, Neale MC, Franz CE, Lyons MJ, Grant MD, Fischl B, Seidman LJ, Tsuang MT, Kremen WS, Dale AM. Hierarchical genetic organization of human cortical surface area. Science. 2012 Mar 30;335(6076):1634-6. PubMed PMID: 22461613; PubMed Central PMCID: PMC3690329. 10. Rimol LM, Nesvåg R, Hagler DJ Jr, Bergmann O, Fennema-Notestine C, Hartberg CB, Haukvik UK, Lange E, Pung CJ, Server A, Melle I, Andreassen OA, Agartz I, Dale AM. Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder. Biol Psychiatry. 2012 Mar 15;71(6):552-60. Epub 2012 Jan 26. PubMed PMID: 22281121. 11. Andreassen OA, Djurovic S, Thompson WK, Schork AJ, Kendler KS, O'Donovan MC, Rujescu D, Werge T, van de Bunt M, Morris AP, McCarthy MI; International Consortium for Blood Pressure GWAS; Diabetes Genetics Replication and Meta-analysis Consortium; Psychiatric Genomics Consortium Schizophrenia Working Group, Roddey JC, McEvoy LK, Desikan RS, Dale AM. Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors. Am J Hum Genet. 2013 Feb 7;92(2):197-209. PubMed PMID: 23375658; PubMed Central PMCID: PMC3567279. 12. Liu JZ, et al. Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis. Nat Genet. 2013 Jun;45(6):670-5. PubMed PMID: 23603763; PubMed Central PMCID: PMC3667736. 13. Schork AJ, Thompson WK, Pham P, Torkamani A, Roddey JC, Sullivan PF, Kelsoe JR, O'Donovan MC, Furberg H, Schork NJ, Andreassen OA, and Dale AM. All SNPs are not created equal: Genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genet. 2013 Apr;9(4):e1003449. PubMed PMID: 23637621; PubMed Central PMCID: PMC3636284. 14. Andreassen OA, Thompson WK, Ripke S, Schork AJ, Mattingsdal M, Kelsoe JR, Kendler KS, O’Donovan MC, Rujescu D, Werge T, Sklar P, The Psychiatric Genomics Consortium (PGC). Bipolar Disorder and Schizophrenia Working Groups, Roddey JC, Chen C-H, McEvoy LK, Desikan RS, Djurovic S, and Dale AM. Improved detection of common variants associated with schizophrenia and bipolar disorder using a pleiotropy-informed stratified false discovery rate method. PLoS Genet. 2013 Apr;9(4):e1003455. doi: 10.1371/journal.pgen.1003455. Epub 2013 Apr 25. PubMed PMID: 23637625; PubMed Central PMCID: PMC3636100. 15. Skranes J, Løhaugen GC, Martinussen M, Håberg A, Brubakk AM, Dale AM. Cortical surface area and IQ in very-low-birth-weight (VLBW) young adults. Cortex. 2013 Sep;49(8):2264-71. PubMed PMID: 23845237.

D. Research Support Ongoing Research Support 5 R01 EB000790-07 Dale (PI) 09/05/2002 - 01/31/2016 NIH (NIBIB) Spatiotemporal Brain Imaging: Microscopic and Systems Level Major Goals are to improve the spatial and temporal resolution of non-invasive technologies which will enable direct imaging of discrete neural units which bridge the systems and cellular levels and to clarify the mechanisms which relate the biophysics of neuronal activity “observables” in imaging measurements.

20114263 Exhibit A-48 Dale (PI) 10/11/2011 - 10/09/2014

General Electric Company Advanced MR Acquisition and Analysis Tools and Techniques The main goal of this project is to develop and validate improved methods for acquisition and analysis of MRI data, including real-time prospective motion correction (PROMO), and Restriction Spectrum Imaging (RSI) for white matter tractography and tumor cell detection.

2 R01 AA013419-11A1 Tapert (PI) 02-01-2002 – 08/31/2018 NIH (NIAAA) Role: Co-Investigator fMRI and Cognition in Youth at Risk for Alcoholism The major goal of this project is to ascertain if indices of brain functioning changes after the onset of heavy drinking to a different degree than observed in typically developing adolescents of the same age who do not use substances.

1 R01 AA021187-01A1 McEvoy (PI) 09/15/2013 – 06/30/2018 NIH (NIAAA) Role: Investigator Association of Alcohol and Nutrition with Cognition and Brain Structure in Aging The goal of this project is to examine the association of past and current alcohol use and nutrition with change in cognitive function over time in older adults, and with neuroimaging measures of late-life brain structural integrity.

1 R01 HD075865-01A1 Akshoomoff (PI) 07/20/2013 – 04/30/2018 NIH (NICHD) Role: Co-Investigator Neural Basis of Emergent Math Difficulties in Healthy Preterm Children The major goal of this study is to track the developmental trajectory in cognitive, academic, and brain measures as very preterm children transition from preschool to formal schooling.

5 R24 HD075489-02 Jernigan (PI) 09/28/2012 – 06/30/2016 HIN (NICHD) Role: Co-Investigator Neurobehavioral Contributors to Math Failure: A Reward-Based Learning Framework The major goal of this study is to initiate a new Learning Disabilities Research Hub focusing initially on high risk for mathematics failure.

5 R01 MH092793-02 Kaye (PI) 05/01/2011 - 02/29/2016 NIH (NIMH) Role: Co-Investigator Monoamine Contributions to Neurocircuitry in Eating Disorders The major goal is to understand the symptoms in AN and BN and contribute to finding better methods for identifying effective medications in these often relapsing and sometimes chronic disorders.

5 U54 MH091657-04 Van Essen (PI) 09/15/2010 – 08/31/2015 NIA/NIHM/NINDS Role: Consortium PI Mapping the Human Connectome: Structure, Function, and Heritability Major goals: To enable analysis, visualization and sharing of HCP data through PING data portal technology.

1 R01 AG034062-01A1 Brewer (PI) 09/01/2011 - 08/31/2015 NIH (NIA) Role: Co-Investigator Sharing Clinical and Imaging Data from ADCS Clinical Trials through BIRN The major goal to use BIRN tools to analyze and share cross-sectional and longitudinal brain imaging data from prior and ongoing ADCS clinical trials.

5 R01 HD061414-03 Jernigan (PI) 09/28/2010 – 07/31/2015 NIH (NICHD) Role: Co-Investigator Mapping Individual Cognitive Differences to Neural Variance and School Readiness The major goal of this study is to track the developmental trajectories in brain measures, and relate these to variations in school readiness in children.

1 R01 MH087563-03 Sowell (PI) 09/21/2010 - 07/31/2015 CHLA – NIH (NIMH) Role: Consortium PI Imaging Brain, Neurocognitive and Pubertal Maturation During Adolescence This project studies adolescent brain development using integrated multimodal neuroimaging, neurocognitive, stress, and hormonal measures longitudinally in typically developing children and adolescents to provide a framework for understanding how risks can tip the balance toward pathological outcomes.

5 R01 HL104118-02 Prisk (PI) 04/01/2011 - 03/31/2015 NIH (NHLBI) Role: Co-Investigator Spatial-Temporal Dynamics of Blood Flow in the Normal Human Lung The overall long-term goal of these studies is to understand the mechanisms by which pulmonary blood flow is controlled, and how that control contributes to gas exchange defects or optimization in health and disease.

U54 NS056883-05 Chang (PI) 09/01/2007 - 08/31/2014 (NCE)

NIH/Univ of Hawaii Role: Consortium PI Imaging Studies in Neurotoxicity and Neurodevelopment The major goal of this project is to better understand the effect of pre-natal exposure to methamphetamine and nicotine on CNS development, using longitudinal MRI scanning of subjects from birth.

5 R01 AG022381-10 Kremen (PI) 09/15/2003 - 08/31/2014 NIH (NIA) Role: Co-Investigator The VETSA Longitudinal MRI Twin Study of Aging Major goals: The major goal of this project is to determine genetic and environmental influences on brain structure and brain aging via MRI. The study will include morphometric analysis of 3-D images, diffusion sensor imaging, and T2*-weighted mapping of hippocampus, and will examine these measures in relation to other measures in the related study listed after this project

5 P50 DA026306-04 Grant (PI) 09/30/2009 - 05/31/2014 NIH (NIDA) Role: Co-Investigator Translational Methamphetamine AIDS Research Center (TMARC) The main goal of the project is to provide scientific leadership, technical support, and opportunities for training to elucidate the combined effects of methamphetamine and HIV infection on the central nervous system.

5 R01 MH042984-20 Kaye (PI) 09/30/1988 - 03/31/2014 NIH (NIMH) Role: Co-Investigator Neurobiology of Anorexia and Bulimia Nervosa The main goal of the project is to study the relationship between Anorexia and Bulimia Nervosa and structural and functional neuroimaging biomarkers.

Completed Research Support

HHSN271200800006C Jernigan (PI) 04/26/2010 - 10/21/2012 (UCI) UC IRVINE Follow-up of the Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (MTA)

5 P50 MH081755-05 Courchesne (PI) 08/01/2007 - 03/31/2013 NIH/NIMH/NICHD Role: PI of Structural Imaging Core Biomarkers of Autism at 12 Months: From Brain Overgrowth to Genes – Project 1: MRI The major goal of this project was to better understand CNS changes in the earliest stages of autism.

5 R01 AG031224-05 Dale (PI) 08/15/2008 - 06/30/2013 NIH/NIA Structural & Metabolic Neuroimaging Biomarkers in Early Alzheimer's Disease Major Goal was to analyze all ADNI structural and metabolic neuroimaging data to characterize morphometric and metabolic changes in early AD.

5 RC2 DA029475-02 Jernigan, Dale (PI) 09/30/2009 – 08/31/2013 NIH (NIDA) Role: Project PI Creating a Pediatric Imaging-Genomics Data Resource The major goals of this project were to assemble a large, cross-sectional imaging-genomics dataset to be used as a shared resource for investigations of genetic bases of neural phenotypes and age-by-genotype interactions that may represent genetically-mediated differences in developmental trajectories.

5 P50 NS022343-24 Trauner (PI) 05/01/1997 - 06/30/2013 NIH (NINDS) Role: PI of Neuroimaging Core. Center for the Study of the Neural Bases of Language and Learning Major goals were to examine perception, attention, memory, language and social cognition in 7-10 year old children with Specific Language Impairment, High Functioning Autism, focal brain lesions, and Williams Syndrome, and compare them to measures of different white matter, cortical and subcortical structures.