David Dill

All Publications

• Reasoning About Vectors: Satisfiability Modulo a Theory of Sequences JOURNAL OF AUTOMATED REASONING Sheng, Y., Notzli, A., Reynolds, A., Zohar, Y., Dill, D., Grieskamp, W., Park, J., Qadeer, S., Barrett, C., Tinelli, C. 2023; 67 (3)

  View details for DOI 10.1007/s10817-023-09682-2

  View details for Web of Science ID 001067178200001

• Reasoning About Vectors Using an SMT Theory of Sequences Sheng, Y., Notzli, A., Reynolds, A., Zohar, Y., Dill, D., Grieskamp, W., Park, J., Qadeer, S., Barrett, C., Tinelli, C., Blanchette, J., Kovacs, L., Pattinson, D. SPRINGER INTERNATIONAL PUBLISHING AG. 2022: 125-143

  View details for DOI 10.1007/978-3-031-10769-6_9

  View details for Web of Science ID 000876376400009

• Reluplex: a calculus for reasoning about deep neural networks FORMAL METHODS IN SYSTEM DESIGN Katz, G., Barrett, C., Dill, D. L., Julian, K., Kochenderfer, M. J. 2021

  View details for DOI 10.1007/s10703-021-00363-7

  View details for Web of Science ID 000668847200001

• Aquila_stLFR: diploid genome assembly based structural variant calling package for stLFR linked-reads. Bioinformatics advances Liu, Y. H., Grubbs, G. L., Zhang, L., Fang, X., Dill, D. L., Sidow, A., Zhou, X. 2021; 1 (1): vbab007

  Abstract

  Identifying structural variants (SVs) is critical in health and disease, however, detecting them remains a challenge. Several linked-read sequencing technologies, including 10X Genomics, TELL-Seq and single tube long fragment read (stLFR), have been recently developed as cost-effective approaches to reconstruct multi-megabase haplotypes (phase blocks) from sequence data of a single sample. These technologies provide an optimal sequencing platform to characterize SVs, though few computational algorithms can utilize them. Thus, we developed Aquila_stLFR, an approach that resolves SVs through haplotype-based assembly of stLFR linked-reads.Aquila_stLFR first partitions long fragment reads into two haplotype-specific blocks with the assistance of the high-quality reference genome, by taking advantage of the potential phasing ability of the linked-read itself. Each haplotype is then assembled independently, to achieve a complete diploid assembly to finally reconstruct the genome-wide SVs. We benchmarked Aquila_stLFR on a well-studied sample, NA24385, and showed Aquila_stLFR can detect medium to large size deletions (50 bp-10 kb) with high sensitivity and medium-size insertions (50 bp-1 kb) with high specificity.Source code and documentation are available on https://github.com/maiziex/Aquila_stLFR.Supplementary data are available at Bioinformatics Advances online.

  View details for DOI 10.1093/bioadv/vbab007

  View details for PubMedID 36700103

  View details for PubMedCentralID PMC9710574

• Aquila enables reference-assisted diploid personal genome assembly and comprehensive variant detection based on linked reads. Nature communications Zhou, X., Zhang, L., Weng, Z., Dill, D. L., Sidow, A. 2021; 12 (1): 1077

  Abstract

  We introduce Aquila, a new approach to variant discovery in personal genomes, which is critical for uncovering the genetic contributions to health and disease. Aquila uses a reference sequence and linked-read data to generate a high quality diploid genome assembly, from which it then comprehensively detects and phases personal genetic variation. The contigs of the assemblies from our libraries cover >95% of the human reference genome, with over 98% of that in a diploid state. Thus, the assemblies support detection and accurate genotyping of the most prevalent types of human genetic variation, including single nucleotide polymorphisms (SNPs), small insertions and deletions (small indels), and structural variants (SVs), in all but the most difficult regions. All heterozygous variants are phased in blocks that can approach arm-level length. The final output of Aquila is a diploid and phased personal genome sequence, and a phased Variant Call Format (VCF) file that also contains homozygous and a few unphased heterozygous variants. Aquila represents a cost-effective approach that can be applied to cohorts for variation discovery or association studies, or to single individuals with rare phenotypes that could be caused by SVs or compound heterozygosity.

  View details for DOI 10.1038/s41467-021-21395-x

  View details for PubMedID 33597536

• The m6A RNA demethylase FTO is a HIF-independent synthetic lethal partner with the VHL tumor suppressor. Proceedings of the National Academy of Sciences of the United States of America Xiao, Y. n., Thakkar, K. N., Zhao, H. n., Broughton, J. n., Li, Y. n., Seoane, J. A., Diep, A. N., Metzner, T. J., von Eyben, R. n., Dill, D. L., Brooks, J. D., Curtis, C. n., Leppert, J. T., Ye, J. n., Peehl, D. M., Giaccia, A. J., Sinha, S. n., Rankin, E. B. 2020

  Abstract

  Loss of the von Hippel-Lindau (VHL) tumor suppressor is a hallmark feature of renal clear cell carcinoma. VHL inactivation results in the constitutive activation of the hypoxia-inducible factors (HIFs) HIF-1 and HIF-2 and their downstream targets, including the proangiogenic factors VEGF and PDGF. However, antiangiogenic agents and HIF-2 inhibitors have limited efficacy in cancer therapy due to the development of resistance. Here we employed an innovative computational platform, Mining of Synthetic Lethals (MiSL), to identify synthetic lethal interactions with the loss of VHL through analysis of primary tumor genomic and transcriptomic data. Using this approach, we identified a synthetic lethal interaction between VHL and the m6A RNA demethylase FTO in renal cell carcinoma. MiSL identified FTO as a synthetic lethal partner of VHL because deletions of FTO are mutually exclusive with VHL loss in pan cancer datasets. Moreover, FTO expression is increased in VHL-deficient ccRCC tumors compared to normal adjacent tissue. Genetic inactivation of FTO using multiple orthogonal approaches revealed that FTO inhibition selectively reduces the growth and survival of VHL-deficient cells in vitro and in vivo. Notably, FTO inhibition reduced the survival of both HIF wild type and HIF-deficient tumors, identifying FTO as an HIF-independent vulnerability of VHL-deficient cancers. Integrated analysis of transcriptome-wide m6A-seq and mRNA-seq analysis identified the glutamine transporter SLC1A5 as an FTO target that promotes metabolic reprogramming and survival of VHL-deficient ccRCC cells. These findings identify FTO as a potential HIF-independent therapeutic target for the treatment of VHL-deficient renal cell carcinoma.

  View details for DOI 10.1073/pnas.2000516117

  View details for PubMedID 32817424

• The Move Prover Zhong, J., Cheang, K., Qadeer, S., Grieskamp, W., Blackshear, S., Park, J., Zohar, Y., Barrett, C., Dill, D. L., Lahiri, S. K., Wang, C. SPRINGER INTERNATIONAL PUBLISHING AG. 2020: 137-150

  View details for DOI 10.1007/978-3-030-53288-8_7

  View details for Web of Science ID 000695276000007

• Mebendazole for Differentiation Therapy of Acute Myeloid Leukemia Identified by a Lineage Maturation Index. Scientific reports Li, Y. n., Thomas, D. n., Deutzmann, A. n., Majeti, R. n., Felsher, D. W., Dill, D. L. 2019; 9 (1): 16775

  Abstract

  Accurate assessment of changes in cellular differentiation status in response to drug treatments or genetic perturbations is crucial for understanding tumorigenesis and developing novel therapeutics for human cancer. We have developed a novel computational approach, the Lineage Maturation Index (LMI), to define the changes in differentiation state of hematopoietic malignancies based on their gene expression profiles. We have confirmed that the LMI approach can detect known changes of differentiation state in both normal and malignant hematopoietic cells. To discover novel differentiation therapies, we applied this approach to analyze the gene expression profiles of HL-60 leukemia cells treated with a small molecule drug library. Among multiple drugs that significantly increased the LMIs, we identified mebendazole, an anti-helminthic clinically used for decades with no known significant toxicity. We tested the differentiation activity of mebendazole using primary leukemia blast cells isolated from human acute myeloid leukemia (AML) patients. We determined that treatment with mebendazole induces dramatic differentiation of leukemia blast cells as shown by cellular morphology and cell surface markers. Furthermore, mebendazole treatment significantly extended the survival of leukemia-bearing mice in a xenograft model. These findings suggest that mebendazole may be utilized as a low toxicity therapeutic for human acute myeloid leukemia and confirm the LMI approach as a robust tool for the discovery of novel differentiation therapies for cancer.

  View details for DOI 10.1038/s41598-019-53290-3

  View details for PubMedID 31727951

• The Marabou Framework for Verification and Analysis of Deep Neural Networks Katz, G., Huang, D. A., Ibeling, D., Julian, K., Lazarus, C., Lim, R., Shah, P., Thakoor, S., Wu, H., Zeljic, A., Dill, D. L., Kochenderfer, M. J., Barrett, C., Dillig, Tasiran, S. SPRINGER INTERNATIONAL PUBLISHING AG. 2019: 443–52

  View details for DOI 10.1007/978-3-030-25540-4_26

  View details for Web of Science ID 000491468000026

• IDH1 Mutant AML Is Susceptible to Targeting De Novo Lipid Synthesis Independent of 2-Hydroxyglutarate and Has a Distinct Metabolic Profile from IDH2 Mutant AML Thomas, D., Nakauchi, Y., Wu, M., Zheng, M., Sinha, S., Dill, D., Peltz, G., Majeti, R. AMER SOC HEMATOLOGY. 2018

  View details for DOI 10.1182/blood-2018-99-115040

  View details for Web of Science ID 000454837601149

• Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. Nature communications Sinha, S., Thomas, D., Chan, S., Gao, Y., Brunen, D., Torabi, D., Reinisch, A., Hernandez, D., Chan, A., Rankin, E. B., Bernards, R., Majeti, R., Dill, D. L. 2017; 8: 15580-?

  Abstract

  Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology by identifying mutation-specific targets and biomarkers.

  View details for DOI 10.1038/ncomms15580

  View details for PubMedID 28561042

• Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data. Nature communications Sinha, S., Thomas, D., Chan, S., Gao, Y., Brunen, D., Torabi, D., Reinisch, A., Hernandez, D., Chan, A., Rankin, E. B., Bernards, R., Majeti, R., Dill, D. L. 2017; 8: 15580-?

  Abstract

  Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology by identifying mutation-specific targets and biomarkers.

  View details for DOI 10.1038/ncomms15580

  View details for PubMedID 28561042

• A geographically-diverse collection of 418 human gut microbiome pathway genome databases SCIENTIFIC DATA Hahn, A. S., Altman, T., Konwar, K. M., Hanson, N. W., Kim, D., Relman, D. A., Dill, D. L., Hallam, S. J. 2017; 4

  Abstract

  Advances in high-throughput sequencing are reshaping how we perceive microbial communities inhabiting the human body, with implications for therapeutic interventions. Several large-scale datasets derived from hundreds of human microbiome samples sourced from multiple studies are now publicly available. However, idiosyncratic data processing methods between studies introduce systematic differences that confound comparative analyses. To overcome these challenges, we developed GutCyc, a compendium of environmental pathway genome databases (ePGDBs) constructed from 418 assembled human microbiome datasets using MetaPathways, enabling reproducible functional metagenomic annotation. We also generated metabolic network reconstructions for each metagenome using the Pathway Tools software, empowering researchers and clinicians interested in visualizing and interpreting metabolic pathways encoded by the human gut microbiome. For the first time, GutCyc provides consistent annotations and metabolic pathway predictions, making possible comparative community analyses between health and disease states in inflammatory bowel disease, Crohn's disease, and type 2 diabetes. GutCyc data products are searchable online, or may be downloaded and explored locally using MetaPathways and Pathway Tools.

  View details for DOI 10.1038/sdata.2017.35

  View details for PubMedID 28398290

• Our Elections Are Not Secure SCIENTIFIC AMERICAN Dill, D. L. 2017; 316 (3): 12

  View details for DOI 10.1038/scientificamerican0317-12

  View details for Web of Science ID 000399228200011

  View details for PubMedID 28207717

• Towards Proving the Adversarial Robustness of Deep Neural Networks ELECTRONIC PROCEEDINGS IN THEORETICAL COMPUTER SCIENCE Katz, G., Barrett, C., Dill, D. L., Julian, K., Kochenderfer, M. J. 2017: 19–26

  View details for DOI 10.4204/EPTCS.257.3

  View details for Web of Science ID 000439354100004

• Reluplex: An Efficient SMT Solver for Verifying Deep Neural Networks Katz, G., Barrett, C., Dill, D. L., Julian, K., Kochenderfer, M. J., Majumdar, R., Kuncak SPRINGER INTERNATIONAL PUBLISHING AG. 2017: 97–117

  View details for DOI 10.1007/978-3-319-63387-9_5

  View details for Web of Science ID 000432196400005

• Isocitrate Dehydrogenase 1 Mutant Cancers Are Metabolically Vulnerable to Inhibition of Acetyl CoA Carboxylase Via a 2-Hydroxyglutarate Independent Mechanism Thomas, D., Sinha, S., Chan, S. M., Wu, M., Torabi, D., Peltz, G., Gao, Y., Dill, D. L., Majeti, R. AMER SOC HEMATOLOGY. 2016

  View details for Web of Science ID 000394446802035

• Cell cycle progression in Caulobacter requires a nucleoid-associated protein with high AT sequence recognition PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Ricci, D. P., Melfi, M. D., Lasker, K., Dill, D. L., McAdams, H. H., Shapiro, L. 2016; 113 (40): E5952-E5961

  Abstract

  Faithful cell cycle progression in the dimorphic bacterium Caulobacter crescentus requires spatiotemporal regulation of gene expression and cell pole differentiation. We discovered an essential DNA-associated protein, GapR, that is required for Caulobacter growth and asymmetric division. GapR interacts with adenine and thymine (AT)-rich chromosomal loci, associates with the promoter regions of cell cycle-regulated genes, and shares hundreds of recognition sites in common with known master regulators of cell cycle-dependent gene expression. GapR target loci are especially enriched in binding sites for the transcription factors GcrA and CtrA and overlap with nearly all of the binding sites for MucR1, a regulator that controls the establishment of swarmer cell fate. Despite constitutive synthesis, GapR accumulates preferentially in the swarmer compartment of the predivisional cell. Homologs of GapR, which are ubiquitous among the α-proteobacteria and are encoded on multiple bacteriophage genomes, also accumulate in the predivisional cell swarmer compartment when expressed in Caulobacter The Escherichia coli nucleoid-associated protein H-NS, like GapR, selectively associates with AT-rich DNA, yet it does not localize preferentially to the swarmer compartment when expressed exogenously in Caulobacter, suggesting that recognition of AT-rich DNA is not sufficient for the asymmetric accumulation of GapR. Further, GapR does not silence the expression of H-NS target genes when expressed in E. coli, suggesting that GapR and H-NS have distinct functions. We propose that Caulobacter has co-opted a nucleoid-associated protein with high AT recognition to serve as a mediator of cell cycle progression.

  View details for DOI 10.1073/pnas.1612579113

  View details for Web of Science ID 000384528900022

  View details for PubMedID 27647925

  View details for PubMedCentralID PMC5056096

• A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury GENETICS Zhang, H., Zheng, M., Wu, M., Xu, D., Nishimura, T., Nishimura, Y., Giffard, R., Xiong, X., Xu, L. J., Clark, J. D., Sahbaie, P., Dill, D. L., Peltz, G. 2016; 203 (1): 599-?

  Abstract

  Haloperidol is an effective antipsychotic agent, but it causes Parkinsonian-like extrapyramidal symptoms in the majority of treated subjects. To address this treatment-limiting toxicity, we analyzed a murine genetic model of haloperidol-induced toxicity (HIT). Analysis of a panel of consomic strains indicated that a genetic factor on chromosome 10 had a significant effect on susceptibility to HIT. We analyzed a whole-genome SNP database to identify allelic variants that were uniquely present on chromosome 10 in the strain that was previously shown to exhibit the highest level of susceptibility to HIT. This analysis implicated allelic variation within pantetheinase genes (Vnn1 and Vnn3), which we propose impaired the biosynthesis of cysteamine, could affect susceptibility to HIT. We demonstrate that administration of cystamine, which is rapidly metabolized to cysteamine, could completely prevent HIT in the murine model. Many of the haloperidol-induced gene expression changes in the striatum of the susceptible strain were reversed by cystamine coadministration. Since cystamine administration has previously been shown to have other neuroprotective actions, we investigated whether cystamine administration could have a broader neuroprotective effect. Cystamine administration caused a 23% reduction in infarct volume after experimentally induced cerebral ischemia. Characterization of this novel pharmacogenetic factor for HIT has identified a new approach for preventing the treatment-limiting toxicity of an antipsychotic agent, which could also be used to reduce the extent of brain damage after stroke.

  View details for DOI 10.1534/genetics.115.184648

  View details for PubMedID 26993135

• The multiple PDZ domain protein Mpdz/MUPP1 regulates opioid tolerance and opioid-induced hyperalgesia BMC GENOMICS Donaldson, R., Sun, Y., Liang, D., Zheng, M., Sahbaie, P., Dill, D. L., Peltz, G., Buck, K. J., Clark, J. D. 2016; 17

  Abstract

  Opioids are a mainstay for the treatment of chronic pain. Unfortunately, therapy-limiting maladaptations such as loss of treatment effect (tolerance), and paradoxical opioid-induced hyperalgesia (OIH) can occur. The objective of this study was to identify genes responsible for opioid tolerance and OIH.These studies used a well-established model of ascending morphine administration to induce tolerance, OIH and other opioid maladaptations in 23 strains of inbred mice. Genome-wide computational genetic mapping was then applied to the data in combination with a false discovery rate filter. Transgenic mice, gene expression experiments and immunoprecipitation assays were used to confirm the functional roles of the most strongly linked gene. The behavioral data processed using computational genetic mapping and false discovery rate filtering provided several strongly linked biologically plausible gene associations. The strongest of these was the highly polymorphic Mpdz gene coding for the post-synaptic scaffolding protein Mpdz/MUPP1. Heterozygous Mpdz +/- mice displayed reduced opioid tolerance and OIH. Mpdz gene expression and Mpdz/MUPP1 protein levels were lower in the spinal cords of low-adapting 129S1/Svlm mice than in high-adapting C57BL/6 mice. Morphine did not alter Mpdz expression levels. In addition, association of Mpdz/MUPP1 with its known binding partner CaMKII did not differ between these high- and low-adapting strains.The degrees of maladaptive changes in response to repeated administration of morphine vary greatly across inbred strains of mice. Variants of the multiple PDZ domain gene Mpdz may contribute to the observed inter-strain variability in tolerance and OIH by virtue of changes in the level of their expression.

  View details for DOI 10.1186/s12864-016-2634-1

  View details for PubMedID 27129385

• CauloBrowser: A systems biology resource for Caulobacter crescentus. Nucleic acids research Lasker, K., Schrader, J. M., Men, Y., Marshik, T., Dill, D. L., McAdams, H. H., Shapiro, L. 2016; 44 (D1): D640-5

  Abstract

  Caulobacter crescentus is a premier model organism for studying the molecular basis of cellular asymmetry. The Caulobacter community has generated a wealth of high-throughput spatiotemporal databases including data from gene expression profiling experiments (microarrays, RNA-seq, ChIP-seq, ribosome profiling, LC-ms proteomics), gene essentiality studies (Tn-seq), genome wide protein localization studies, and global chromosome methylation analyses (SMRT sequencing). A major challenge involves the integration of these diverse data sets into one comprehensive community resource. To address this need, we have generated CauloBrowser (www.caulobrowser.org), an online resource for Caulobacter studies. This site provides a user-friendly interface for quickly searching genes of interest and downloading genome-wide results. Search results about individual genes are displayed as tables, graphs of time resolved expression profiles, and schematics of protein localization throughout the cell cycle. In addition, the site provides a genome viewer that enables customizable visualization of all published high-throughput genomic data. The depth and diversity of data sets collected by the Caulobacter community makes CauloBrowser a unique and valuable systems biology resource.

  View details for DOI 10.1093/nar/gkv1050

  View details for PubMedID 26476443

  View details for PubMedCentralID PMC4702786

• CauloBrowser: A systems biology resource for Caulobacter crescentus. Nucleic acids research Lasker, K., Schrader, J. M., Men, Y., Marshik, T., Dill, D. L., McAdams, H. H., Shapiro, L. 2016; 44 (D1): D640-5

  Abstract

  Caulobacter crescentus is a premier model organism for studying the molecular basis of cellular asymmetry. The Caulobacter community has generated a wealth of high-throughput spatiotemporal databases including data from gene expression profiling experiments (microarrays, RNA-seq, ChIP-seq, ribosome profiling, LC-ms proteomics), gene essentiality studies (Tn-seq), genome wide protein localization studies, and global chromosome methylation analyses (SMRT sequencing). A major challenge involves the integration of these diverse data sets into one comprehensive community resource. To address this need, we have generated CauloBrowser (www.caulobrowser.org), an online resource for Caulobacter studies. This site provides a user-friendly interface for quickly searching genes of interest and downloading genome-wide results. Search results about individual genes are displayed as tables, graphs of time resolved expression profiles, and schematics of protein localization throughout the cell cycle. In addition, the site provides a genome viewer that enables customizable visualization of all published high-throughput genomic data. The depth and diversity of data sets collected by the Caulobacter community makes CauloBrowser a unique and valuable systems biology resource.

  View details for DOI 10.1093/nar/gkv1050

  View details for PubMedID 26476443

  View details for PubMedCentralID PMC4702786

• Deciphering Cancer Biology using Boolean Methods Sinha, S., Dill, D. L., IEEE IEEE. 2016: 150–54

  View details for Web of Science ID 000389035600022

• Boolean Implication Mining for Synthetic Lethal Interactions in AML Identifies Acetyl-CoA Carboxylase As a Synthetic Lethal Partner of the IDH1 mutation Sinha, S., Thomas, D., Chan, S. M., Gao, Y., Jansen, R., Majeti, R., Dill, D. L. AMER SOC HEMATOLOGY. 2015

  View details for Web of Science ID 000368019004204

• Discovery of differentiation therapeutics using a systems biology approach Li, Y., Seita, J., Felsher, D., Dill, D. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.TRANSCAGEN-A2-35

  View details for Web of Science ID 000370972600082

• A systems biology approach for the discovery of differentiation therapeutics Li, Y., Seita, J., Felsher, D., Dill, D. L. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.COMPSYSBIO-B2-12

  View details for Web of Science ID 000370971000059

• Deciphering the cancer methylome with Boolean implications to find novel drivers of aberrant DNA methylation and actionable drug targets Sinha, S., Thomas, D., Majeti, R., Dill, D. L. AMER ASSOC CANCER RESEARCH. 2015

  View details for DOI 10.1158/1538-7445.COMPSYSBIO-B2-20

  View details for Web of Science ID 000370971000065

• Towards in vivo estimation of reaction kinetics using high-throughput metabolomics data: a maximum likelihood approach BMC SYSTEMS BIOLOGY Zhang, W., Kolte, R., Dill, D. L. 2015; 9

  Abstract

  High-throughput assays such as mass spectrometry have opened up the possibility for large-scale in vivo measurements of the metabolome. This data could potentially be used to estimate kinetic parameters for many metabolic reactions. However, high-throughput in vivo measurements have special properties that are not taken into account in existing methods for estimating kinetic parameters, including significant relative errors in measurements of metabolite concentrations and reaction rates, and reactions with multiple substrates and products, which are sometimes reversible. A new method is needed to estimate kinetic parameters taking into account these factors.A new method, InVEst (In Vivo Estimation), is described for estimating reaction kinetic parameters, which addresses the specific challenges of in vivo data. InVEst uses maximum likelihood estimation based on a model where all measurements have relative errors. Simulations show that InVEst produces accurate estimates for a reversible enzymatic reaction with multiple reactants and products, that estimated parameters can be used to predict the effects of genetic variants, and that InVEst is more accurate than general least squares and graphic methods on data with relative errors. InVEst uses the bootstrap method to evaluate the accuracy of its estimates.InVEst addresses several challenges of in vivo data, which are not taken into account by existing methods. When data have relative errors, InVEst produces more accurate and robust estimates. InVEst also provides useful information about estimation accuracy using bootstrapping. It has potential applications of quantifying the effects of genetic variants, inference of the target of a mutation or drug treatment and improving flux estimation.

  View details for DOI 10.1186/s12918-015-0214-7

  View details for Web of Science ID 000362397100001

  View details for PubMedID 26437964

  View details for PubMedCentralID PMC4595320

• The role of Abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans. PLoS medicine Zheng, M., Zhang, H., Dill, D. L., Clark, J. D., Tu, S., Yablonovitch, A. L., Tan, M. H., Zhang, R., Rujescu, D., Wu, M., Tessarollo, L., Vieira, W., Gottesman, M. M., Deng, S., Eberlin, L. S., Zare, R. N., Billard, J., Gillet, J., Li, J. B., Peltz, G. 2015; 12 (2)

  Abstract

  We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.

  View details for DOI 10.1371/journal.pmed.1001782

  View details for PubMedID 25647612

• The role of abcb5 alleles in susceptibility to haloperidol-induced toxicity in mice and humans. PLoS medicine Zheng, M., Zhang, H., Dill, D. L., Clark, J. D., Tu, S., Yablonovitch, A. L., Tan, M. H., Zhang, R., Rujescu, D., Wu, M., Tessarollo, L., Vieira, W., Gottesman, M. M., Deng, S., Eberlin, L. S., Zare, R. N., Billard, J., Gillet, J., Li, J. B., Peltz, G. 2015; 12 (2): e1001782

  Abstract

  We know very little about the genetic factors affecting susceptibility to drug-induced central nervous system (CNS) toxicities, and this has limited our ability to optimally utilize existing drugs or to develop new drugs for CNS disorders. For example, haloperidol is a potent dopamine antagonist that is used to treat psychotic disorders, but 50% of treated patients develop characteristic extrapyramidal symptoms caused by haloperidol-induced toxicity (HIT), which limits its clinical utility. We do not have any information about the genetic factors affecting this drug-induced toxicity. HIT in humans is directly mirrored in a murine genetic model, where inbred mouse strains are differentially susceptible to HIT. Therefore, we genetically analyzed this murine model and performed a translational human genetic association study.A whole genome SNP database and computational genetic mapping were used to analyze the murine genetic model of HIT. Guided by the mouse genetic analysis, we demonstrate that genetic variation within an ABC-drug efflux transporter (Abcb5) affected susceptibility to HIT. In situ hybridization results reveal that Abcb5 is expressed in brain capillaries, and by cerebellar Purkinje cells. We also analyzed chromosome substitution strains, imaged haloperidol abundance in brain tissue sections and directly measured haloperidol (and its metabolite) levels in brain, and characterized Abcb5 knockout mice. Our results demonstrate that Abcb5 is part of the blood-brain barrier; it affects susceptibility to HIT by altering the brain concentration of haloperidol. Moreover, a genetic association study in a haloperidol-treated human cohort indicates that human ABCB5 alleles had a time-dependent effect on susceptibility to individual and combined measures of HIT. Abcb5 alleles are pharmacogenetic factors that affect susceptibility to HIT, but it is likely that additional pharmacogenetic susceptibility factors will be discovered.ABCB5 alleles alter susceptibility to HIT in mouse and humans. This discovery leads to a new model that (at least in part) explains inter-individual differences in susceptibility to a drug-induced CNS toxicity.

  View details for DOI 10.1371/journal.pmed.1001782

  View details for PubMedID 25647612

  View details for PubMedCentralID PMC4315575

• Mutant WT1 is associated with DNA hypermethylation of PRC2 targets in AML and responds to EZH2 inhibition. Blood Sinha, S., Thomas, D., Yu, L., Gentles, A. J., Jung, N., Corces-Zimmerman, M. R., Chan, S. M., Reinisch, A., Feinberg, A. P., Dill, D. L., Majeti, R. 2015; 125 (2): 316-326

  Abstract

  Acute myeloid leukemia (AML) is associated with deregulation of DNA methylation; however, many cases do not bear mutations in known regulators of CpG methylation. We found that mutations in WT1, IDH2, and CEBPA were strongly linked to DNA hypermethylation in AML using a novel integrative analysis of TCGA data based on Boolean implications, if-then rules that identify all individual CpG sites that are hypermethylated in the presence of a mutation. Introduction of mutant WT1 (WT1mut) into wildtype AML cells induced DNA hypermethylation, confirming mutant WT1 to be causally associated with DNA hypermethylation. Methylated genes in WT1mut primary patient samples were highly enriched for polycomb repressor complex 2 (PRC2) targets, implicating PRC2 dysregulation in WT1mut leukemogenesis. We found that PRC2 target genes were aberrantly repressed in WT1mut AML, and that expression of mutant WT1 in CD34+ cord blood cells induced myeloid differentiation block. Treatment of WT1mut AML cells with shRNA or pharmacologic PRC2/EZH2 inhibitors promoted myeloid differentiation, suggesting EZH2 inhibitors may be active in this AML subtype. Our results highlight a strong association between mutant WT1 and DNA hypermethylation in AML, and demonstrate that Boolean implications can be used to decipher mutation-specific methylation patterns that may lead to therapeutic insights.

  View details for DOI 10.1182/blood-2014-03-566018

  View details for PubMedID 25398938

• The global regulatory architecture of transcription during the Caulobacter cell cycle. PLoS genetics Zhou, B., Schrader, J. M., Kalogeraki, V. S., Abeliuk, E., Dinh, C. B., Pham, J. Q., Cui, Z. Z., Dill, D. L., McAdams, H. H., Shapiro, L. 2015; 11 (1)

  Abstract

  Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5' RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, measured their transcription levels at multiple times in the cell cycle, and identified their transcription factor binding sites. Out of 2726 TSSs, 586 were shown to be cell cycle-regulated and we identified 529 binding sites for the cell cycle master regulators. Twenty-three percent of the cell cycle-regulated promoters were found to be under the combinatorial control of two or more of the global regulators. Previously unknown features of the core cell cycle circuit were identified, including 107 antisense TSSs which exhibit cell cycle-control, and 241 genes with multiple TSSs whose transcription levels often exhibited different cell cycle timing. Cumulatively, this study uncovered novel new layers of transcriptional regulation mediating the bacterial cell cycle.

  View details for DOI 10.1371/journal.pgen.1004831

  View details for PubMedID 25569173

  View details for PubMedCentralID PMC4287350

• The Global Regulatory Architecture of Transcription during the Caulobacter Cell Cycle. PLoS genetics Zhou, B., Schrader, J. M., Kalogeraki, V. S., Abeliuk, E., Dinh, C. B., Pham, J. Q., Cui, Z. Z., Dill, D. L., McAdams, H. H., Shapiro, L. 2015; 11 (1)

  View details for DOI 10.1371/journal.pgen.1004831

  View details for PubMedID 25569173

• Towards in vivo estimation of reaction kinetics using high-throughput metabolomics data: a maximum likelihood approach. BMC systems biology Zhang, W., Kolte, R., Dill, D. L. 2015; 9: 66-?

  Abstract

  High-throughput assays such as mass spectrometry have opened up the possibility for large-scale in vivo measurements of the metabolome. This data could potentially be used to estimate kinetic parameters for many metabolic reactions. However, high-throughput in vivo measurements have special properties that are not taken into account in existing methods for estimating kinetic parameters, including significant relative errors in measurements of metabolite concentrations and reaction rates, and reactions with multiple substrates and products, which are sometimes reversible. A new method is needed to estimate kinetic parameters taking into account these factors.A new method, InVEst (In Vivo Estimation), is described for estimating reaction kinetic parameters, which addresses the specific challenges of in vivo data. InVEst uses maximum likelihood estimation based on a model where all measurements have relative errors. Simulations show that InVEst produces accurate estimates for a reversible enzymatic reaction with multiple reactants and products, that estimated parameters can be used to predict the effects of genetic variants, and that InVEst is more accurate than general least squares and graphic methods on data with relative errors. InVEst uses the bootstrap method to evaluate the accuracy of its estimates.InVEst addresses several challenges of in vivo data, which are not taken into account by existing methods. When data have relative errors, InVEst produces more accurate and robust estimates. InVEst also provides useful information about estimation accuracy using bootstrapping. It has potential applications of quantifying the effects of genetic variants, inference of the target of a mutation or drug treatment and improving flux estimation.

  View details for DOI 10.1186/s12918-015-0214-7

  View details for PubMedID 26437964

  View details for PubMedCentralID PMC4595320

• Leukemia Cell Differentiation upon Targeted Therapy Revealed By a Systems Biology Approach Li, Y., Seita, J., Felsher, D. W., Dill, D. AMER SOC HEMATOLOGY. 2014

  View details for Web of Science ID 000349242708179

• MYC through miR-17-92 Suppresses Specific Target Genes to Maintain Survival, Autonomous Proliferation, and a Neoplastic State. Cancer cell Li, Y., Choi, P. S., Casey, S. C., Dill, D. L., Felsher, D. W. 2014; 26 (2): 262-272

  Abstract

  The MYC oncogene regulates gene expression through multiple mechanisms, and its overexpression culminates in tumorigenesis. MYC inactivation reverses turmorigenesis through the loss of distinguishing features of cancer, including autonomous proliferation and survival. Here we report that MYC via miR-17-92 maintains a neoplastic state through the suppression of chromatin regulatory genes Sin3b, Hbp1, Suv420h1, and Btg1, as well as the apoptosis regulator Bim. The enforced expression of miR-17-92 prevents MYC suppression from inducing proliferative arrest, senescence, and apoptosis and abrogates sustained tumor regression. Knockdown of the five miR-17-92 target genes blocks senescence and apoptosis while it modestly delays proliferative arrest, thus partially recapitulating miR-17-92 function. We conclude that MYC, via miR-17-92, maintains a neoplastic state by suppressing specific target genes.

  View details for DOI 10.1016/j.ccr.2014.06.014

  View details for PubMedID 25117713

• Automated identification of stratifying signatures in cellular subpopulations PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Bruggner, R. V., Bodenmiller, B., Dill, D. L., Tibshirani, R. J., Nolan, G. P. 2014; 111 (26): E2770-E2777

  Abstract

  Elucidation and examination of cellular subpopulations that display condition-specific behavior can play a critical contributory role in understanding disease mechanism, as well as provide a focal point for development of diagnostic criteria linking such a mechanism to clinical prognosis. Despite recent advancements in single-cell measurement technologies, the identification of relevant cell subsets through manual efforts remains standard practice. As new technologies such as mass cytometry increase the parameterization of single-cell measurements, the scalability and subjectivity inherent in manual analyses slows both analysis and progress. We therefore developed Citrus (cluster identification, characterization, and regression), a data-driven approach for the identification of stratifying subpopulations in multidimensional cytometry datasets. The methodology of Citrus is demonstrated through the identification of known and unexpected pathway responses in a dataset of stimulated peripheral blood mononuclear cells measured by mass cytometry. Additionally, the performance of Citrus is compared with that of existing methods through the analysis of several publicly available datasets. As the complexity of flow cytometry datasets continues to increase, methods such as Citrus will be needed to aid investigators in the performance of unbiased--and potentially more thorough--correlation-based mining and inspection of cell subsets nested within high-dimensional datasets.

  View details for DOI 10.1073/pnas.1408792111

  View details for Web of Science ID 000338118900020

  View details for PubMedCentralID PMC4084463

• Automated identification of stratifying signatures in cellular subpopulations. Proceedings of the National Academy of Sciences of the United States of America Bruggner, R. V., Bodenmiller, B., Dill, D. L., Tibshirani, R. J., Nolan, G. P. 2014; 111 (26): E2770-7

  Abstract

  Elucidation and examination of cellular subpopulations that display condition-specific behavior can play a critical contributory role in understanding disease mechanism, as well as provide a focal point for development of diagnostic criteria linking such a mechanism to clinical prognosis. Despite recent advancements in single-cell measurement technologies, the identification of relevant cell subsets through manual efforts remains standard practice. As new technologies such as mass cytometry increase the parameterization of single-cell measurements, the scalability and subjectivity inherent in manual analyses slows both analysis and progress. We therefore developed Citrus (cluster identification, characterization, and regression), a data-driven approach for the identification of stratifying subpopulations in multidimensional cytometry datasets. The methodology of Citrus is demonstrated through the identification of known and unexpected pathway responses in a dataset of stimulated peripheral blood mononuclear cells measured by mass cytometry. Additionally, the performance of Citrus is compared with that of existing methods through the analysis of several publicly available datasets. As the complexity of flow cytometry datasets continues to increase, methods such as Citrus will be needed to aid investigators in the performance of unbiased--and potentially more thorough--correlation-based mining and inspection of cell subsets nested within high-dimensional datasets.

  View details for DOI 10.1073/pnas.1408792111

  View details for PubMedID 24979804

• Mining TCGA data using Boolean implications. PloS one Sinha, S., Tsang, E. K., Zeng, H., Meister, M., Dill, D. L. 2014; 9 (7)

  Abstract

  Boolean implications (if-then rules) provide a conceptually simple, uniform and highly scalable way to find associations between pairs of random variables. In this paper, we propose to use Boolean implications to find relationships between variables of different data types (mutation, copy number alteration, DNA methylation and gene expression) from the glioblastoma (GBM) and ovarian serous cystadenoma (OV) data sets from The Cancer Genome Atlas (TCGA). We find hundreds of thousands of Boolean implications from these data sets. A direct comparison of the relationships found by Boolean implications and those found by commonly used methods for mining associations show that existing methods would miss relationships found by Boolean implications. Furthermore, many relationships exposed by Boolean implications reflect important aspects of cancer biology. Examples of our findings include cis relationships between copy number alteration, DNA methylation and expression of genes, a new hierarchy of mutations and recurrent copy number alterations, loss-of-heterozygosity of well-known tumor suppressors, and the hypermethylation phenotype associated with IDH1 mutations in GBM. The Boolean implication results used in the paper can be accessed at http://crookneck.stanford.edu/microarray/TCGANetworks/.

  View details for DOI 10.1371/journal.pone.0102119

  View details for PubMedID 25054200

  View details for PubMedCentralID PMC4108374

• Mining TCGA Data Using Boolean Implications. PloS one Sinha, S., Tsang, E. K., Zeng, H., Meister, M., Dill, D. L. 2014; 9 (7)

  View details for DOI 10.1371/journal.pone.0102119

  View details for PubMedID 25054200

• Liquid chromatography/mass spectrometry methods for measuring dipeptide abundance in non-small-cell lung cancer. Rapid communications in mass spectrometry : RCM Wu, M., Xu, Y., Fitch, W. L., Zheng, M., Merritt, R. E., Shrager, J. B., Zhang, W., Dill, D. L., Peltz, G., Hoang, C. D. 2013; 27 (18): 2091-2098

  Abstract

  Metabolomic profiling is a promising methodology of identifying candidate biomarkers for disease detection and monitoring. Although lung cancer is among the leading causes of cancer-related mortality worldwide, the lung tumor metabolome has not been fully characterized.We utilized a targeted metabolomic approach to analyze discrete groups of related metabolites. We adopted a dansyl [5-(dimethylamino)-1-naphthalene sulfonamide] derivatization with liquid chromatography/mass spectrometry (LC/MS) to analyze changes of metabolites from paired tumor and normal lung tissues. Identification of dansylated dipeptides was confirmed with synthetic standards. A systematic analysis of retention times was required to reliably identify isobaric dipeptides. We validated our findings in a separate sample cohort.We produced a database of the LC retention times and MS/MS spectra of 361 dansyl dipeptides. Interpretation of the spectra is presented. Using this standard data, we identified a total of 279 dipeptides in lung tumor tissue. The abundance of 90 dipeptides was selectively increased in lung tumor tissue compared to normal tissue. In a second set of validation tissues, 12 dipeptides were selectively increased.A systematic evaluation of certain metabolite classes in lung tumors may identify promising disease-specific metabolites. Our database of all possible dipeptides will facilitate ongoing translational applications of metabolomic profiling as it relates to lung cancer. Copyright © 2013 John Wiley & Sons, Ltd.

  View details for DOI 10.1002/rcm.6656

  View details for PubMedID 23943330

• Identification of drug targets by chemogenomic and metabolomic profiling in yeast PHARMACOGENETICS AND GENOMICS Wu, M., Zheng, M., Zhang, W., Suresh, S., Schlecht, U., Fitch, W. L., Aronova, S., Baumann, S., Davis, R., St Onge, R., Dill, D. L., Peltz, G. 2012; 22 (12): 877-886

  Abstract

  To advance our understanding of disease biology, the characterization of the molecular target for clinically proven or new drugs is very important. Because of its simplicity and the availability of strains with individual deletions in all of its genes, chemogenomic profiling in yeast has been used to identify drug targets. As measurement of drug-induced changes in cellular metabolites can yield considerable information about the effects of a drug, we investigated whether combining chemogenomic and metabolomic profiling in yeast could improve the characterization of drug targets.We used chemogenomic and metabolomic profiling in yeast to characterize the target for five drugs acting on two biologically important pathways. A novel computational method that uses a curated metabolic network was also developed, and it was used to identify the genes that are likely to be responsible for the metabolomic differences found.The combination of metabolomic and chemogenomic profiling, along with data analyses carried out using a novel computational method, could robustly identify the enzymes targeted by five drugs. Moreover, this novel computational method has the potential to identify genes that are causative of metabolomic differences or drug targets.

  View details for DOI 10.1097/FPC.0b013e32835aa888

  View details for Web of Science ID 000311031800006

  View details for PubMedID 23076370

• Computational genetic discoveries that could improve perioperative medicine CURRENT OPINION IN ANESTHESIOLOGY Zheng, M., Dill, D., Clark, J. D., Peltz, G. 2012; 25 (4): 428-433

  Abstract

  The review examines the rationale and translational utility of computational genetic studies using murine models of biomedical traits.Computational genetic mapping studies have identified the genetic basis for biomedical trait differences in 16 different murine models, including several that are of importance to perioperative medicine.The results have generated new treatments for alleviating incisional pain and narcotic drug withdrawal symptoms, which are now in clinical trials. A recent study identified allelic differences affecting chronic pain responses in mice and humans, which may enable a new 'personalized' approach to treating chronic pain.

  View details for DOI 10.1097/ACO.0b013e32835561f9

  View details for PubMedID 22647490

• Gene Expression Commons: An Open Platform for Absolute Gene Expression Profiling PLOS ONE Seita, J., Sahoo, D., Rossi, D. J., Bhattacharya, D., Serwold, T., Inlay, M. A., Ehrlich, L. I., Fathman, J. W., Dill, D. L., Weissman, I. L. 2012; 7 (7)

  Abstract

  Gene expression profiling using microarrays has been limited to comparisons of gene expression between small numbers of samples within individual experiments. However, the unknown and variable sensitivities of each probeset have rendered the absolute expression of any given gene nearly impossible to estimate. We have overcome this limitation by using a very large number (>10,000) of varied microarray data as a common reference, so that statistical attributes of each probeset, such as the dynamic range and threshold between low and high expression, can be reliably discovered through meta-analysis. This strategy is implemented in a web-based platform named "Gene Expression Commons" (https://gexc.stanford.edu/) which contains data of 39 distinct highly purified mouse hematopoietic stem/progenitor/differentiated cell populations covering almost the entire hematopoietic system. Since the Gene Expression Commons is designed as an open platform, investigators can explore the expression level of any gene, search by expression patterns of interest, submit their own microarray data, and design their own working models representing biological relationship among samples.

  View details for DOI 10.1371/journal.pone.0040321

  View details for Web of Science ID 000306548900020

  View details for PubMedID 22815738

  View details for PubMedCentralID PMC3399844

• Cd14 SNPs regulate the innate immune response MOLECULAR IMMUNOLOGY Liu, H., Hu, Y., Zheng, M., Suhoski, M. M., Engleman, E. G., Dill, D. L., Hudnall, M., Wang, J., Spolski, R., Leonard, W. J., Peltz, G. 2012; 51 (2): 112-127

  Abstract

  CD14 is a monocytic differentiation antigen that regulates innate immune responses to pathogens. Here, we show that murine Cd14 SNPs regulate the length of Cd14 mRNA and CD14 protein translation efficiency, and consequently the basal level of soluble CD14 (sCD14) and type I IFN production by murine macrophages. This has substantial downstream consequences for the innate immune response; the level of expression of at least 40 IFN-responsive murine genes was altered by this mechanism. We also observed that there was substantial variation in the length of human CD14 mRNAs and in their translation efficiency. sCD14 increased cytokine production by human dendritic cells (DCs), and sCD14-primed DCs augmented human CD4T cell proliferation. These findings may provide a mechanism for exploring the complex relationship between CD14 SNPs, serum sCD14 levels, and susceptibility to human infectious and allergic diseases.

  View details for DOI 10.1016/j.molimm.2012.02.112

  View details for Web of Science ID 000304687500002

  View details for PubMedID 22445606

  View details for PubMedCentralID PMC3341513

• A better prognosis for genetic association studies in mice TRENDS IN GENETICS Zheng, M., Dill, D., Peltz, G. 2012; 28 (2): 62-69

  Abstract

  Although inbred mouse strains have been the premier model organism used in biomedical research, multiple studies and analyses have indicated that genome-wide association studies (GWAS) cannot be productively performed using inbred mouse strains. However, there is one type of GWAS in mice that has successfully identified the genetic basis for many biomedical traits of interest: haplotype-based computational genetic mapping (HBCGM). Here, we describe how the methodological basis for a HBCGM study significantly differs from that of a conventional murine GWAS, and how an integrative analysis of its output within the context of other 'omic' information can enable genetic discovery. Consideration of these factors will substantially improve the prognosis for the utility of murine genetic association studies for biomedical discovery.

  View details for DOI 10.1016/j.tig.2011.10.006

  View details for Web of Science ID 000300532200002

  View details for PubMedID 22118772

  View details for PubMedCentralID PMC3268904

• Cd14 SNPs regulate the innate immune response Molecular Immunology Lu, H., Hu, Y., Zheng, M., Engleman, E., Dill, D., Hudnall, M. 2012; 2 (51): 112–127
• Computational genetic discoveries that could improve perioperative medicine Current Opinion in Anesthesiology Zheng, M., Dill, D., Clark, J., Peltz, G. 2012
• Gene Expression Commons: an open platform for absolute gene expression profiliing PLoS One Seita, J., Sahoo, D., Rossi, D., Bhattacharya, D., Serwold, T., Inlay, M., Dill, D. 2012; 7
• A better prognosis for genetic association studies in mice Trends in Genetics Zheng, M., Dill, D., Peltz, G. 2012; 2 (28): 62–69
• Identification of drug targets by chemogenomic and metabolomic profiling in yeast. Pharmacogenetic Genomics Wu, M., Zheng, M., Zhang, W., Suresh, S., Schlecht, U., Fitch, W. L., Dill, D. 2012
• Next-Generation Computational Genetic Analysis: Multiple Complement Alleles Control Survival after Candida albicans Infection INFECTION AND IMMUNITY Peltz, G., Zaas, A. K., Zheng, M., Solis, N. V., Zhang, M. X., Liu, H., Hu, Y., Boxx, G. M., Phan, Q. T., Dill, D., Filler, S. G. 2011; 79 (11): 4472-4479

  Abstract

  Candida albicans is a fungal pathogen that causes severe disseminated infections that can be lethal in immunocompromised patients. Genetic factors are known to alter the initial susceptibility to and severity of C. albicans infection. We developed a next-generation computational genetic mapping program with advanced features to identify genetic factors affecting survival in a murine genetic model of hematogenous C. albicans infection. This computational tool was used to analyze the median survival data after inbred mouse strains were infected with C. albicans, which provides a useful experimental model for identification of host susceptibility factors. The computational analysis indicated that genetic variation within early classical complement pathway components (C1q, C1r, and C1s) could affect survival. Consistent with the computational results, serum C1 binding to this pathogen was strongly affected by C1rs alleles, as was survival of chromosome substitution strains. These results led to a combinatorial, conditional genetic model, involving an interaction between C5 and C1r/s alleles, which accurately predicted survival after infection. Beyond applicability to infectious disease, this information could increase our understanding of the genetic factors affecting susceptibility to autoimmune and neurodegenerative diseases.

  View details for DOI 10.1128/IAI.05666-11

  View details for Web of Science ID 000296352400018

  View details for PubMedID 21875959

  View details for PubMedCentralID PMC3257944

• Are Cells Asynchronous Circuits? (Invited Talk) 12th International Conference on Verification, Model Checking, and Abstract Interpretation Dill, D. L. SPRINGER-VERLAG BERLIN. 2011: 1–1

  View details for Web of Science ID 000297039800001

• Next-generation computational genetic analysis: Multiple complement alleles control survival after candida albicans infection Infection and Immunity Peltz, G., Zaas, A., K., Zheng, M., Solis, N., V., Zhang, M., X., Liu, H., H., Dill, D. 2011; 11 (79): 4472–4479
• The Role of Interleukin-1 in Wound Biology. Part II: In Vivo and Human Translational Studies ANESTHESIA AND ANALGESIA Hu, Y., Liang, D., Li, X., Liu, H., Zhang, X., Zheng, M., Dill, D., Shi, X., Qiao, Y., Yeomans, D., Carvalho, B., Angst, M. S., Clark, J. D., Peltz, G. 2010; 111 (6): 1534-1542

  Abstract

  In the accompanying paper, we demonstrate that genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production through altering the amount of interleukin (IL)-1 produced. We further investigate the role of IL-1 in incisional wound biology and its effect on wound chemokine production in vivo and whether this mechanism could be active in human subjects.A well-characterized murine model of incisional wounding was used to assess the in vivo role of IL-1 in wound biology. The amount of 7 different cytokines/chemokines produced within an experimentally induced skin incision on a mouse paw and the nociceptive response was analyzed in mice treated with an IL-1 inhibitor. We also investigated whether human IL-1β or IL-1α stimulated the production of chemokines by primary human keratinocytes in vitro, and whether there was a correlation between IL-1β and chemokine levels in 2 experimental human wound paradigms.Administration of an IL-1 receptor antagonist to mice decreased the nociceptive response to an incisional wound, and reduced the production of multiple inflammatory mediators, including keratinocyte-derived chemokine (KC) and macrophage inhibitory protein (MIP)-1α, within the wounds. IL-1α and IL-1β stimulated IL-8 and GRO-α (human homologues of murine keratinocyte-derived chemokine) production by primary human keratinocytes in vitro. IL-1β levels were highly correlated with IL-8 in human surgical wounds, and at cutaneous sites of human ultraviolet B-induced sunburn injury.IL-1 plays a major role in regulating inflammatory mediator production in wounds through a novel mechanism; by stimulating the production of multiple cytokines and chemokines, it impacts clinically important aspects of wound biology. These data suggest that administration of an IL-1 receptor antagonist within the perioperative period could decrease postsurgical wound pain.

  View details for DOI 10.1213/ANE.0b013e3181f691eb

  View details for PubMedID 20889944

• The Role of Interleukin-1 in Wound Biology. Part I: Murine In Silico and In Vitro Experimental Analysis ANESTHESIA AND ANALGESIA Hu, Y., Liang, D., Li, X., Liu, H., Zhang, X., Zheng, M., Dill, D., Shi, X., Qiao, Y., Yeomans, D., Carvalho, B., Angst, M. S., Clark, J. D., Peltz, G. 2010; 111 (6): 1525-1533

  Abstract

  Wound healing is a multistep, complex process that involves the coordinated action of multiple cell types. Conflicting results have been obtained when conventional methods have been used to study wound biology. Therefore, we analyzed the wound response in a mouse genetic model.We analyzed inflammatory mediators produced within incisional wounds induced in 16 inbred mouse strains. Computational haplotype-based genetic analysis of inter-strain differences in the level of production of 2 chemokines in wounds was performed. An in vitro experimental analysis system was developed to investigate whether interleukin (IL)-1 could affect chemokine production by 2 different types of cells that are present within wounds.The level of 2 chemokines, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein 1α, exhibited very large (75- and 463-fold, respectively) interstrain differences within wound tissue across this inbred strain panel. Genetic variation within Nalp1, an inflammasome component that regulates IL-1 production, correlated with the interstrain differences in KC and macrophage inhibitory protein 1α production. Consistent with the genetic correlation, IL-1β was shown to stimulate KC production by murine keratinocyte and fibroblast cell lines in vitro.Genetic variation within Nalp1 could contribute to interstrain differences in wound chemokine production by altering the amount of IL-1 produced.

  View details for DOI 10.1213/ANE.0b013e3181f5ef5a

  View details for PubMedID 20889942

• Towards Program Optimization through Automated Analysis of Numerical Precision. Proceedings of the ... CGO : International Symposium on Code Generation and Optimization. International Symposium on Code Generation and Optimization Linderman, M. D., Ho, M., Dill, D. L., Meng, T. H., Nolan, G. P. 2010; 2010: 230-237

  Abstract

  Reducing the arithmetic precision of a computation has real performance implications, including increased speed, decreased power consumption, and a smaller memory footprint. For some architectures, e.g., GPUs, there can be such a large performance difference that using reduced precision is effectively a requirement. The tradeoff is that the accuracy of the computation will be compromised. In this paper we describe a proof assistant and associated static analysis techniques for efficiently bounding numerical and precision-related errors. The programmer/compiler can use these bounds to numerically verify and optimize an application for different input and machine configurations. We present several case study applications that demonstrate the effectiveness of these techniques and the performance benefits that can be achieved with rigorous precision analysis.

  View details for DOI 10.1145/1772954.1772987

  View details for PubMedID 28804690

  View details for PubMedCentralID PMC5552069

• MiDReG: A method of mining developmentally regulated genes using Boolean implications PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Sahoo, D., Seita, J., Bhattacharya, D., Inlay, M. A., Weissman, I. L., Plevritis, S. K., Dill, D. L. 2010; 107 (13): 5732-5737

  Abstract

  We present a method termed mining developmentally regulated genes (MiDReG) to predict genes whose expression is either activated or repressed as precursor cells differentiate. MiDReG does not require gene expression data from intermediate stages of development. MiDReG is based on the gene expression patterns between the initial and terminal stages of the differentiation pathway, coupled with "if-then" rules (Boolean implications) mined from large-scale microarray databases. MiDReG uses two gene expression-based seed conditions that mark the initial and the terminal stages of a given differentiation pathway and combines the statistically inferred Boolean implications from these seed conditions to identify the relevant genes. The method was validated by applying it to B-cell development. The algorithm predicted 62 genes that are expressed after the KIT+ progenitor cell stage and remain expressed through CD19+ and AICDA+ germinal center B cells. qRT-PCR of 14 of these genes on sorted B-cell progenitors confirmed that the expression of 10 genes is indeed stably established during B-cell differentiation. Review of the published literature of knockout mice revealed that of the predicted genes, 63.4% have defects in B-cell differentiation and function and 22% have a role in the B cell according to other experiments, and the remaining 14.6% are not characterized. Therefore, our method identified novel gene candidates for future examination of their role in B-cell development. These data demonstrate the power of MiDReG in predicting functionally important intermediate genes in a given developmental pathway that is defined by a mutually exclusive gene expression pattern.

  View details for DOI 10.1073/pnas.0913635107

  View details for PubMedID 20231483

• Timing Robustness in the Budding and Fission Yeast Cell Cycles PLOS ONE Mangla, K., Dill, D. L., Horowitz, M. A. 2010; 5 (2)

  Abstract

  Robustness of biological models has emerged as an important principle in systems biology. Many past analyses of Boolean models update all pending changes in signals simultaneously (i.e., synchronously), making it impossible to consider robustness to variations in timing that result from noise and different environmental conditions. We checked previously published mathematical models of the cell cycles of budding and fission yeast for robustness to timing variations by constructing Boolean models and analyzing them using model-checking software for the property of speed independence. Surprisingly, the models are nearly, but not totally, speed-independent. In some cases, examination of timing problems discovered in the analysis exposes apparent inaccuracies in the model. Biologically justified revisions to the model eliminate the timing problems. Furthermore, in silico random mutations in the regulatory interactions of a speed-independent Boolean model are shown to be unlikely to preserve speed independence, even in models that are otherwise functional, providing evidence for selection pressure to maintain timing robustness. Multiple cell cycle models exhibit strong robustness to timing variation, apparently due to evolutionary pressure. Thus, timing robustness can be a basis for generating testable hypotheses and can focus attention on aspects of a model that may need refinement.

  View details for DOI 10.1371/journal.pone.0008906

  View details for Web of Science ID 000274209700002

  View details for PubMedID 20126540

  View details for PubMedCentralID PMC2813865

• The role of interleukin-1 in wound biology. part i: murine in silico and in vitro experimental analysis Anesthesia & Analgesia Hu, Y., Liang, D., Li, X., Liu, H., Zhang, X., Zheng, M., Dill, D. 2010; 6 (111): 1525–1533
• Timing robustness in the budding and fission yeast cell cycles PLoS ONE Mangla, K., Dill, D. L., Horowitz, M. A. 2010; 2 (5): e8906
• The role of interleukin-1 in wound biology. part ii: in vivo and human translational studies Anesthesia & nalgesia Hu, Y., Liang, D., Li, X., Liu, H., Zhang, X., Zheng, M., Dill, D. 2010; 6 (111): 1534–1542
• Gene expression changes induced by genistein in the prostate cancer cell line lncap Open Prostate Cancer J Bhamre, S., Sahoo, D., Tibshirani, R., Dill, D., L., Brooks, J., D 2010; 3: 86–98
• Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development GENES & DEVELOPMENT Inlay, M. A., Bhattacharya, D., Sahoo, D., Serwold, T., Seita, J., Karsunky, H., Plevritis, S. K., Dill, D. L., Weissman, I. L. 2009; 23 (20): 2376-2381

  Abstract

  Common lymphoid progenitors (CLPs) clonally produce both B- and T-cell lineages, but have little myeloid potential in vivo. However, some studies claim that the upstream lymphoid-primed multipotent progenitor (LMPP) is the thymic seeding population, and suggest that CLPs are primarily B-cell-restricted. To identify surface proteins that distinguish functional CLPs from B-cell progenitors, we used a new computational method of Mining Developmentally Regulated Genes (MiDReG). We identified Ly6d, which divides CLPs into two distinct populations: one that retains full in vivo lymphoid potential and produces more thymocytes at early timepoints than LMPP, and another that behaves essentially as a B-cell progenitor.

  View details for DOI 10.1101/gad.1836009

  View details for PubMedID 19833765

• Identification of the branchopoint between B and T cell development through MiDReG Inlay, M. A., Bhattacharya, D., Sahoo, D., Seita, J., Karsunky, H., Serwold, T., Plevritis, S., Dill, D., Weissman, I. L. AMER ASSOC IMMUNOLOGISTS. 2009

  View details for Web of Science ID 000209763603052

• Temporal Changes in Gene Expression Induced by Sulforaphane in Human Prostate Cancer Cells PROSTATE Bhamre, S., Sahoo, D., Tibshirani, R., Dill, D. L., Brooks, J. D. 2009; 69 (2): 181-190

  Abstract

  Prostate cancer is thought to arise as a result of oxidative stresses and induction of antioxidant electrophile defense (phase 2) enzymes has been proposed as a prostate cancer prevention strategy. The isothiocyanate sulforaphane, derived from cruciferous vegetables like broccoli, potently induces surrogate markers of phase 2 enzyme activity in prostate cells in vitro and in vivo. To better understand the temporal effects of sulforaphane and broccoli sprouts on gene expression in prostate cells, we carried out comprehensive transcriptome analysis using cDNA microarrays.Transcripts significantly modulated by sulforaphane over time were identified using StepMiner analysis. Ingenuity Pathway Analysis (IPA) was used to identify biological pathways, networks, and functions significantly altered by sulforaphane treatment.StepMiner and IPA revealed significant changes in many transcripts associated with cell growth and cell cycle, as well as a significant number associated with cellular response to oxidative damage and stress. Comparison to an existing dataset suggested that sulforaphane blocked cell growth by inducing G2/M arrest. Cell growth assays and flow cytometry analysis confirmed that sulforaphane inhibited cell growth and induced cell cycle arrest.Our data suggest that in prostate cells sulforaphane primarily induces cellular defenses and inhibits cell growth by causing G2/M phase arrest. Furthermore, based on the striking similarities in the gene expression patterns induced across experiments in these cells, sulforaphane appears to be the primary bioactive compound present in broccoli sprouts, suggesting that broccoli sprouts can serve as a suitable source for sulforaphane in intervention trials.

  View details for DOI 10.1002/pros.20869

  View details for Web of Science ID 000262701200008

  View details for PubMedID 18973173

  View details for PubMedCentralID PMC2612096

• Temporal changes in gene expression induced by sulforaphane in human prostate cancer cells The Prostate Bhamre, S., Sahoo, D., Tibshirani, R., Dill, D., Brooks, J. 2009; 2 (69): 181–90
• Ly6d marks the earliest stage of b-cell specification and identifies the branchpoint between b-cell and t-cell development Genes and Development Inlay, Matthew, A., Bhattacharya, D., Sahoo, D., Serwold, T., Seita, J., Karsunky, H., Dill, D. 2009; 20 (23): 2376–2381
• EXE: Automatically Generating Inputs of Death 13th ACM Conference on Computer and Communications Security Cadar, C., Ganesh, V., Pawlowski, P. M., Dill, D. L., Engler, D. R. ASSOC COMPUTING MACHINERY. 2008

  View details for DOI 10.1145/1455518.1455522

  View details for Web of Science ID 000263100000004

• Point/Counterpoint The U. S. Should Ban Paperless Electronic Voting Machines COMMUNICATIONS OF THE ACM Dill, D. L. 2008; 51 (10): 29-30

  View details for DOI 10.1145/1400181.1400192

  View details for Web of Science ID 000259930000019

• Architecture and inherent robustness of a bacterial cell-cycle control system PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Shen, X., Collier, J., Dill, D., Shapiro, L., Horowitz, M., McAdams, H. H. 2008; 105 (32): 11340-11345

  Abstract

  A closed-loop control system drives progression of the coupled stalked and swarmer cell cycles of the bacterium Caulobacter crescentus in a near-mechanical step-like fashion. The cell-cycle control has a cyclical genetic circuit composed of four regulatory proteins with tight coupling to processive chromosome replication and cell division subsystems. We report a hybrid simulation of the coupled cell-cycle control system, including asymmetric cell division and responses to external starvation signals, that replicates mRNA and protein concentration patterns and is consistent with observed mutant phenotypes. An asynchronous sequential digital circuit model equivalent to the validated simulation model was created. Formal model-checking analysis of the digital circuit showed that the cell-cycle control is robust to intrinsic stochastic variations in reaction rates and nutrient supply, and that it reliably stops and restarts to accommodate nutrient starvation. Model checking also showed that mechanisms involving methylation-state changes in regulatory promoter regions during DNA replication increase the robustness of the cell-cycle control. The hybrid cell-cycle simulation implementation is inherently extensible and provides a promising approach for development of whole-cell behavioral models that can replicate the observed functionality of the cell and its responses to changing environmental conditions.

  View details for DOI 10.1073/pnas.0805258105

  View details for Web of Science ID 000258560700056

  View details for PubMedID 18685108

  View details for PubMedCentralID PMC2516238

• Genomic and proteomic analysis reveals a threshold level of MYC required for tumor maintenance CANCER RESEARCH Shachaf, C. M., Gentles, A. J., Elchuri, S., Sahoo, D., Soen, Y., Sharpe, O., Perez, O. D., Chang, M., Mitchel, D., Robinson, W. H., Dill, D., Nolan, G. P., Plevritis, S. K., Felsher, D. W. 2008; 68 (13): 5132-5142

  Abstract

  MYC overexpression has been implicated in the pathogenesis of most types of human cancers. MYC is likely to contribute to tumorigenesis by its effects on global gene expression. Previously, we have shown that the loss of MYC overexpression is sufficient to reverse tumorigenesis. Here, we show that there is a precise threshold level of MYC expression required for maintaining the tumor phenotype, whereupon there is a switch from a gene expression program of proliferation to a state of proliferative arrest and apoptosis. Oligonucleotide microarray analysis and quantitative PCR were used to identify changes in expression in 3,921 genes, of which 2,348 were down-regulated and 1,573 were up-regulated. Critical changes in gene expression occurred at or near the MYC threshold, including genes implicated in the regulation of the G(1)-S and G(2)-M cell cycle checkpoints and death receptor/apoptosis signaling. Using two-dimensional protein analysis followed by mass spectrometry, phospho-flow fluorescence-activated cell sorting, and antibody arrays, we also identified changes at the protein level that contributed to MYC-dependent tumor regression. Proteins involved in mRNA translation decreased below threshold levels of MYC. Thus, at the MYC threshold, there is a loss of its ability to maintain tumorigenesis, with associated shifts in gene and protein expression that reestablish cell cycle checkpoints, halt protein translation, and promote apoptosis.

  View details for DOI 10.1158/0008-5472.CAN-07-6192

  View details for PubMedID 18593912

• Combined Analysis of Murine and Human Microarrays and ChIP Analysis Reveals Genes Associated with the Ability of MYC To Maintain Tumorigenesis PLOS GENETICS Wu, C., Sahoo, D., Arvanitis, C., Bradon, N., Dill, D. L., Felsher, D. W. 2008; 4 (6)

  Abstract

  The MYC oncogene has been implicated in the regulation of up to thousands of genes involved in many cellular programs including proliferation, growth, differentiation, self-renewal, and apoptosis. MYC is thought to induce cancer through an exaggerated effect on these physiologic programs. Which of these genes are responsible for the ability of MYC to initiate and/or maintain tumorigenesis is not clear. Previously, we have shown that upon brief MYC inactivation, some tumors undergo sustained regression. Here we demonstrate that upon MYC inactivation there are global permanent changes in gene expression detected by microarray analysis. By applying StepMiner analysis, we identified genes whose expression most strongly correlated with the ability of MYC to induce a neoplastic state. Notably, genes were identified that exhibited permanent changes in mRNA expression upon MYC inactivation. Importantly, permanent changes in gene expression could be shown by chromatin immunoprecipitation (ChIP) to be associated with permanent changes in the ability of MYC to bind to the promoter regions. Our list of candidate genes associated with tumor maintenance was further refined by comparing our analysis with other published results to generate a gene signature associated with MYC-induced tumorigenesis in mice. To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format. One large functional group of these genes included the ribosomal structural proteins. In addition, we identified a group of genes involved in a diverse array of cellular functions including: BZW2, H2AFY, SFRS3, NAP1L1, NOLA2, UBE2D2, CCNG1, LIFR, FABP3, and EDG1. Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis.

  View details for DOI 10.1371/journal.pgen.1000090

  View details for Web of Science ID 000260410300026

  View details for PubMedID 18535662

  View details for PubMedCentralID PMC2390767

• Boolean implication networks derived from large scale, whole genome microarray datasets GENOME BIOLOGY Sahoo, D., Dill, D. L., Gentles, A. J., Tibshirani, R., Plevritis, S. K. 2008; 9 (10)

  Abstract

  We describe a method for extracting Boolean implications (if-then relationships) in very large amounts of gene expression microarray data. A meta-analysis of data from thousands of microarrays for humans, mice, and fruit flies finds millions of implication relationships between genes that would be missed by other methods. These relationships capture gender differences, tissue differences, development, and differentiation. New relationships are discovered that are preserved across all three species.

  View details for PubMedID 18973690

• Boolean implication networks derived from large scale, whole genome microarray datasets Genome Biology Sahoo, D., Dill, D., L., Gentles, A., J., Tibshirani, R., Plevritis, S., K. 2008; 10 (9): R157
• Architecture and inherent robustness of a bacterial cell-cycle control system Proceedings of the National Academy of Sciences Shen, X., Collier, J., Dill, D., L., Shapiro, L., Horowitz, M., McAdams, H., H. 2008; 32 (105): 11340–11345
• EXE: automatically generating inputs of death. ACM Transactions on Information and System Security Cadar, C., Ganesh, V., Pawlowski, Peter, M., Dill, David, L., Engler, Dawson, R. 2008; 2 (12)
• Combined analysis of murine and human microarrays and chip analysis reveals genes associated with the ability of myc to maintain tumorigenesis. PLoS Genetics Wu, C., H., Sahoo, D., Arvanitis, C., Bradon, N., Dill, D., L., Felsher, D., W. 2008; 6 (4)
• Genomic and proteomic analysis reveals a threshold level of myc required for tumor maintenance Cancer Research Shachaf, C., M., Gentles, A., J., Elchuri, S., Sahoo, D., Soen, Y., Sharpe, O., Dill, D. 2008; 13 (68): 5132
• Automatic Formal Verification of Block Cipher Implementations 8th International Conference on Formal Methods in Computer-Aided Design Smith, E. W., Dill, D. L. IEEE. 2008: 45–51

  View details for Web of Science ID 000265244800006

• A retrospective on Mur phi Symposium on 25 Years of Model Checking (25MC) Dill, D. L. SPRINGER-VERLAG BERLIN. 2008: 77–88

  View details for Web of Science ID 000257623600005

• Extracting binary signals from microarray time-course data NUCLEIC ACIDS RESEARCH Sahoo, D., Dill, D. L., Tibshirani, R., Plevritis, S. K. 2007; 35 (11): 3705-3712

  Abstract

  This article presents a new method for analyzing microarray time courses by identifying genes that undergo abrupt transitions in expression level, and the time at which the transitions occur. The algorithm matches the sequence of expression levels for each gene against temporal patterns having one or two transitions between two expression levels. The algorithm reports a P-value for the matching pattern of each gene, and a global false discovery rate can also be computed. After matching, genes can be sorted by the direction and time of transitions. Genes can be partitioned into sets based on the direction and time of change for further analysis, such as comparison with Gene Ontology annotations or binding site motifs. The method is evaluated on simulated and actual time-course data. On microarray data for budding yeast, it is shown that the groups of genes that change in similar ways and at similar times have significant and relevant Gene Ontology annotations.

  View details for DOI 10.1093/nar/gkm284

  View details for PubMedID 17517782

• A decision procedure for bit-vectors and arrays 19th International Conference on Computer Aided Verification Ganesh, V., Dill, D. L. SPRINGER-VERLAG BERLIN. 2007: 519–531

  View details for Web of Science ID 000248222700049

• A retrospective on murφ In 25 years of Model Checking, volume 4925 of Lecture Notes in Computer Science Dill, David, L. 2007: 1
• Extracting boolean signals from microarray time course data. Nucleic Acids Research Sahoo, D., Dill, David, L., Tibshirani, R., Plevritis, Sylvia, K. 2007; 11 (35): 3705–3712
• The Pathalyzer: A tool for analysis of signal transduction pathways Joint Annual Workshop on Systems Biology and on Regulatory Genomics Dill, D. L., Knapp, M. A., Gage, P., Talcott, C., Laderoute, K., Lincoln, P. SPRINGER-VERLAG BERLIN. 2007: 11–22

  View details for Web of Science ID 000244806900002

• A refinement method for validity checking of quantified first-order formulas in hardware verification 6th International Conference on Formal Methods in Computer Aided Design Abu-Haimed, H., Dill, D. L., Berezin, S. IEEE COMPUTER SOC. 2006: 145–152

  View details for Web of Science ID 000243594800019

• Multiple representations of biological processes. Transactions on Computational Systems Biology Talcott, C., Dill, David, L. 2006: 221–245
• Multiple representations of biological processes 4th International Conference on Computational Methods in Systems Biology Talcott, C., Dill, D. L. SPRINGER-VERLAG BERLIN. 2006: 221–245

  View details for Web of Science ID 000244723500010

• A Practical Approach to Partial Functions in CVC Lite ELECTRONIC NOTES IN THEORETICAL COMPUTER SCIENCE Berezin, S., Barrett, C., Shikanian, I., Chechik, M., Gurfinkel, A., Dill, D. L. 2005; 125 (3): 13–23

  View details for DOI 10.1016/j.entcs.2004.06.064

  View details for Web of Science ID 000214005200003

• The pathway logic assistant Talcott, C., Dill, David, L. 2005
• Evaluation of voting systems. Commun. ACM Vora, P., L., Adida, B., Bucholz, R., Chaum, D., Dill, D., L., Jefferson, D. 2004; 11 (47): 144
• A partitioning methodology for BDD-based verification 5th International Conference on Formal Methods in Computer-Aided Design (FMCAD) Sahoo, D., Iyer, S., Jain, J., Stangier, C., Narayan, A., Dill, D. L., Emerson, E. A. SPRINGER-VERLAG BERLIN. 2004: 399–413

  View details for Web of Science ID 000225877900028

• A practical approach to partial functions in CVC Lite. Barrett, C., Berezin, S., Shikanian, I., Chechik, M., Gurfinkel, A., Dill, David, L. 2004
• A partitioning methodology for bdd-based verification Sahoo, D., Iyer, Subramanian, K., Jain, J., Stangier, C., Narayan, A., Dill, David, L. 2004
• Guest editors' introduction: E-voting security. IEEE Security and Privacy Dill, David, L., Rubin, Aviel, D. 2004; 1 (2)
• A proof-producing boolean search engine. Barrett, C., Berezin, S., Dill, David, L. 2003
• Using formal specifications for functional validation of hardware designs IEEE DESIGN & TEST OF COMPUTERS Shimizu, K., Dill, D. L. 2002; 19 (4): 96-106

  View details for Web of Science ID 000176582000014

• Efficient algorithms for approximate time separation of events SADHANA-ACADEMY PROCEEDINGS IN ENGINEERING SCIENCES Chakraborty, S., Dill, D. L., Yun, K. Y. 2002; 27: 129-162

  View details for Web of Science ID 000177265700002

• Formal verification of out-of-order execution with incremental flushing FORMAL METHODS IN SYSTEM DESIGN Jones, R. B., Skakkebaek, J. U., Dill, D. L. 2002; 20 (2): 139-158

  View details for Web of Science ID 000173803400002

• Counter-example based predicate discovery in predicate abstraction 4th International Conference on Formal Methods in Computer-Aided Design (FMCAD 2002) Das, S., Dill, D. L. SPRINGER-VERLAG BERLIN. 2002: 19–32

  View details for Web of Science ID 000182825700002

• CVC: a Cooperating Validity Checker. Stump, A., Barrett, C., Dill, D. 2002
• Checking Satisfiability of First-Order Formulas by Incremental Translation to SAT. Barrett, Clark, W., Dill, David, L., Stump, A. edited by Brinksma, E., Larsen, K. G. 2002
• Using formal specifications for functional validation of hardware designs IEEE Design & Test of Computers Shimizu, K., Dill, David, L. 2002; 4 (19): 96–106
• Deriving a simulation input generator and a coverage metric from a formal specification 39th Design Automation Conference Shimizu, K., Dill, D. L. ASSOC COMPUTING MACHINERY. 2002: 801–806

  View details for Web of Science ID 000177213300141

• Deciding Presburger arithmetic by model checking and comparisons with other methods 4th International Conference on Formal Methods in Computer-Aided Design (FMCAD 2002) Ganesh, V., Berezin, S., Dill, D. L. SPRINGER-VERLAG BERLIN. 2002: 171–186

  View details for Web of Science ID 000182825700011

• Parallelizing the Mur phi verifier 9th International Conference on Computer-Aided Verification (CAV 97) Stern, U., Dill, D. L. SPRINGER. 2001: 117–29

  View details for Web of Science ID 000167827700003

• A simple method for extracting models from protocol code 28th Annual International Symposium on Computer Architecture Lie, D., Chou, A., Engler, D., Dill, D. L. IEEE COMPUTER SOC. 2001: 192–203

  View details for Web of Science ID 000170768200017

• A decision procedure for an extensional theory of arrays 16th Annual IEEE Symposium on Logic in Computer Science Stump, A., Barrett, C. W., Dill, D. L., LEVITT, J. IEEE COMPUTER SOC. 2001: 29–37

  View details for Web of Science ID 000170688700004

• Successive approximation of abstract transition relations 16th Annual IEEE Symposium on Logic in Computer Science Das, S., Dill, D. L. IEEE COMPUTER SOC. 2001: 51–58

  View details for Web of Science ID 000170688700006

• Automatic checking of aggregation abstractions through state enumeration IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Park, S., Das, S., Dill, D. L. 2000; 19 (10): 1202-1210

  View details for Web of Science ID 000089953200010

• Monitor-based formal specification of PCI 3rd International Conference on Formal Methods in Computer-Aided Design Shimizu, K., Dill, D. L., Hu, A. J. SPRINGER-VERLAG BERLIN. 2000: 335–353

  View details for Web of Science ID 000174608800020

• Reliable verification using symbolic simulation with scalar values 37th Annual Design Automation Conference (DAC) Wilson, C., Dill, D. L. ASSOC COMPUTING MACHINERY. 2000: 124–129

  View details for Web of Science ID 000166739300025

• Counterexample-guided choice of projections in approximate symbolic model checking IEEE/ACM International Conference on Computer Aided Design (ICCAD-2000) Govindaraju, S. G., Dill, D. L. IEEE. 2000: 115–119

  View details for Web of Science ID 000166023200020

• Java model checking 15th IEEE International Conference on Automated Software Engineering (ASE 2000) Park, D. Y., Stern, U., Skakkebaek, J. U., Dill, D. L. IEEE COMPUTER SOC. 2000: 253–256

  View details for Web of Science ID 000089913800027

• Symbolic simulation with approximate values 3rd International Conference on Formal Methods in Computer-Aided Design Wilson, C., Dill, D. L., Bryant, R. E. SPRINGER-VERLAG BERLIN. 2000: 470–485

  View details for Web of Science ID 000174608800028

• A framework for cooperating decision procedures 17th International Conference on Automated Deduction (CADE-17) Barrett, C. W., Dill, D. L., Stump, A. SPRINGER-VERLAG BERLIN. 2000: 79–98

  View details for Web of Science ID 000166717300006

• Timing analysis of asynchronous systems using time separation of events IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Chakraborty, S. A., Yun, K. Y., Dill, D. L. 1999; 18 (8): 1061-1076

  View details for Web of Science ID 000081585500001

• Verifying systems with replicated components in Mur phi FORMAL METHODS IN SYSTEM DESIGN Ip, C. N., Dill, D. L. 1999; 14 (3): 273-310

  View details for Web of Science ID 000080735800004

• Automatic synthesis of extended burst-mode circuits: Part I (specification and hazard-free implementations) IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Yun, K. Y., Dill, D. L. 1999; 18 (2): 101-117

  View details for Web of Science ID 000078407000002

• An executable specification and verifier for relaxed memory order IEEE TRANSACTIONS ON COMPUTERS Park, S. J., Dill, D. L. 1999; 48 (2): 227-235

  View details for Web of Science ID 000079060200015

• Min-max timing analysis and an application to asynchronous circuits PROCEEDINGS OF THE IEEE Chakraborty, S., Dill, D. L., Yun, K. Y. 1999; 87 (2): 332-346

  View details for Web of Science ID 000078216900011

• Automatic synthesis of extended burst-mode circuits: Part II (automatic synthesis) IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Yun, K. Y., Dill, D. L. 1999; 18 (2): 118-132

  View details for Web of Science ID 000078407000003

• Timing analysis of asynchronous systems using time separation of events. IEEE Transactions on Computer-Aided Design Chakraborty, S., Yun, Kenneth, Y., Dill, David, L. 1999; 8 (18): 1061–1076
• Experience with predicate abstraction. Das, S., Dill, David, L., Park, S. 1999
• Automatic synthesis of extended burst-mode circuits: Part I (specification and hazard-free implementations). IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems Yun, Kenneth, Y., Dill, David, L. 1999; 2 (18): 101–117
• Improved approximate reachability using auxiliary state variables. Govindaraju, Shankar, G., Dill, David, L., Bergmann, Jules, P. 1999
• Automatic synthesis of extended burst-mode circuits: Part II (specification and hazard-free implementations). IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems Yun, Kenneth, Y., Dill, David, L. 1999; 2 (18): 118–132
• An executable specification, analyzer and verifier for RMO (relaxed memory order). IEEE Transactions on Computers Park, S., Dill, David, L. 1999; 2 (48): 227–335
• Verifying systems with replicated components in Murφ. Formal Methods in System Design Ip, C., Norris., Dill, David, L. 1999; 3 (14): 41–75
• BDD-based synthesis of extended burst-mode controllers IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Yun, K. Y., Lin, B., Dill, D. L., Devadas, S. 1998; 17 (9): 782-792

  View details for Web of Science ID 000076096100004

• Verification of cache coherence protocols by aggregation of distributed transactions 8th Annual ACM Symposium on Parallel Algorithms and Architectures Park, S., Dill, D. L. SPRINGER. 1998: 355–76

  View details for Web of Science ID 000074349800003

• Using magnetic disk instead of main memory in the Mur phi verifier 10th International Conference on Computer-Aided Verification (CAV 98) Stern, U., Dill, D. L. SPRINGER-VERLAG BERLIN. 1998: 172–183

  View details for Web of Science ID 000083172700018

• Reducing manual abstraction in formal verification of out-of-order execution. Jones, Robert, B., Skakkebæk, Jens, U., Dill, David, L. edited by Gopalakrishnan, G., Windley, P. 1998
• Verification of cache coherence protocols by aggregation of distributed transactions. Theory of Computing Systems Park, S., Dill, David, L. 1998; 4 (31): 355–376
• Bdd-based synthesis of extended burst-mode controllers. IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems Yun, Kenneth, Y., Lin, B., Dill, David, L., Devadas, S. 1998; 9 (17): 782–792
• Formally verifying data and control with weak reachability invariants. Su, Jeffrey, X., Dill, David, L., Skakkebæk, Jens, U. edited by Gopalakrishnan, G., Windley, P. 1998
• Checking properties of safety critical specifications using efficient decision procedures. Park, David, Y.W., Skakkebæk, Jens, U., Heimdahl, Mats, P.E., Czerny, Barbara, J., Dill, David, L. 1998
• A decision procedure for bit-vector arithmetic 35th Design Automation Conference Barrett, C. W., Dill, D. L., LEVITT, J. R. ASSOC COMPUTING MACHINERY. 1998: 522–527

  View details for Web of Science ID 000077273700094

• Verification by approximate forward and backward reachability IEEE/ACM International Conference on Computer-Aided Design Govindaraju, S. G., Dill, D. L. ASSOC COMPUTING MACHINERY. 1998: 366–370

  View details for Web of Science ID 000077729800056

• Static analysis to identify invariants in RSML specifications 5th International Symposium on Formal Techniques in Real-Time and Fault-Tolerant Systems (FTRTFT 98) Park, D. Y., Skakkebaek, J. U., Dill, D. L. SPRINGER-VERLAG BERLIN. 1998: 133–142

  View details for Web of Science ID 000082522000013

• Format verification of out-of-order execution using incremental flushing 10th International Conference on Computer-Aided Verification (CAV 98) Skakkebaek, J. U., Jones, R. B., Dill, D. L. SPRINGER-VERLAG BERLIN. 1998: 98–109

  View details for Web of Science ID 000083172700012

• Practical timing analysis of asynchronous circuits using time separation of events IEEE Custom Integrated Circuits Conference Chakraborty, S., Yun, K. Y., Dill, D. L. IEEE. 1998: 455–458

  View details for Web of Science ID 000075218500094

• Approximate reachability with BDDs using overlapping projections 35th Design Automation Conference Govindaraju, S. G., Dill, D. L., Hu, A. J., Horowitz, M. A. ASSOC COMPUTING MACHINERY. 1998: 451–456

  View details for Web of Science ID 000077273700081

• What's between simulation and formal verification? (Extended abstract) 35th Design Automation Conference Dill, D. L. ASSOC COMPUTING MACHINERY. 1998: 328–329

  View details for Web of Science ID 000077273700058

• Validation with guided search of the state space 35th Design Automation Conference Yang, C. H., Dill, D. L. ASSOC COMPUTING MACHINERY. 1998: 599–604

  View details for Web of Science ID 000077273700108

• Timing analysis for extended burst-mode circuits 3rd International Symposium on Advanced Research in Asynchronous Circuits and Systems Chakraborty, S., Dill, D. L., Yun, K. Y., Chang, K. Y. I E E E, COMPUTER SOC PRESS. 1997: 101–111

  View details for Web of Science ID A1997BH63Q00010

• Approximate algorithms for time separation of events 1997 IEEE/ACM International Conference on Computer-Aided Design (ICCAD 97) Chakraborty, S., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1997: 190–194

  View details for Web of Science ID A1997BK01U00030

• More accurate polynomial-time min-max timing simulation 3rd International Symposium on Advanced Research in Asynchronous Circuits and Systems Chakraborty, S., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1997: 112–123

  View details for Web of Science ID A1997BH63Q00011

• Parallelizing the Mur phi verifier 9th International Conference on Computer-Aided Verification (CAV 97) Stern, U., Dill, D. L. SPRINGER-VERLAG BERLIN. 1997: 256–267

  View details for Web of Science ID 000075410600026

• Better verification through symmetry FORMAL METHODS IN SYSTEM DESIGN Ip, C. N., Dill, D. L. 1996; 9 (1-2): 41-75

  View details for Web of Science ID A1996VE93600003

• State reduction using reversible rules 33rd Design Automation Conference Ip, C. N., Dill, D. L. ASSOC COMPUTING MACHINERY. 1996: 564–567

  View details for Web of Science ID A1996BF92A00112

• Verification of flash cache coherence protocol by aggregation of distributed actions. Park, S., Dill, David, L. 1996
• Combining state space caching and hash compaction. In Methoden des Entwurfs und der Verifikation digitaler Systeme, 4. GI/ITG/GME Workshop Stern, U., Dill, D., L. 1996
• Formal methods: state of the art and future directions. ACM Computing Surveys Clarke, E., M., Wing, J., M., Alur, R., Cleaveland, R., Dill, D., Emerson, A. 1996; 4 (28): 626–43
• The murφ verification system. Dill, David, L. 1996
• Protocol verification by aggregation of distributed transactions. Park, S., Dill, David, L. 1996
• A new scheme for memory-efficient probabilistic verification. Stern, U., Dill, David, L. 1996
• Automata-theoretic verification of real-time systems. Formal Methods for Real-time Computing, number 5 in Trends in Software Alur, R., Dill, David, L. edited by Heitmeyer, C., Mandrioli, D. 1996: 55–81
• Protocol verification by aggregation of distributed actions. Park, S., Dill, David, L. 1996
• Combining state space caching and hash compaction. Stern, U., Dill, David, L. 1996
• Better verification through symmetry. Formal Methods in System Design Ip, C., Norris., Dill, David, L. 1996; 1–2 (9): 41–75
• Validity checking for combinations of theories with equality 1st International Conference on Formal Methods in Computer-Aided Design (FMCAD 96) Barrett, C., Dill, D., LEVITT, J. SPRINGER-VERLAG BERLIN. 1996: 187–201

  View details for Web of Science ID 000073935500013

• Self-consistency checking 1st International Conference on Formal Methods in Computer-Aided Design (FMCAD 96) Jones, R. B., Seger, C. J., Dill, D. L. SPRINGER-VERLAG BERLIN. 1996: 159–171

  View details for Web of Science ID 000073935500011

• Automatic generation of invariants in processor verification 1st International Conference on Formal Methods in Computer-Aided Design (FMCAD 96) Su, J. X., Dill, D. L., Barrett, C. W. SPRINGER-VERLAG BERLIN. 1996: 377–388

  View details for Web of Science ID 000073935500027

• EXACT 2-LEVEL MINIMIZATION OF HAZARD-FREE LOGIC WITH MULTIPLE-INPUT CHANGES IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Nowick, S. M., Dill, D. L. 1995; 14 (8): 986-997

  View details for Web of Science ID A1995RL43500007

• Architecture validation for processors 22nd Annual International Symposium on Computer Architecture Ho, R. C., Yang, C. H., Horowitz, M. A., Dill, D. L. ASSOC COMPUTING MACHINERY. 1995: 404–413

  View details for Web of Science ID A1995BE13F00036

• A high-performance asynchronous SCSI controller International Conference on Computer Design - VLSI in Computers and Processors (ICCD 95) Yun, K. Y., Dill, D. L. IEEE COMPUTER SOC. 1995: 44–49

  View details for Web of Science ID A1995BE54G00007

• Exact two-level minimization of hazard-free logic with multiple-input changes. IEEE Transactions on Computer-Aided Design of Integrated Circuits Nowick, S., M., Dill, D., L. 1995; 8 (14): 986–997
• A high-performance asynchronous SCSI controller. Yun, Kenneth, Y., Dill, David, L. 1995
• A theory of timed automata. Theoretical Computer Science Alur, R., Dill, D., L. 1995; 126: 183–235
• Efficient validity checking for processor verification 1995 IEEE/ACM International Conference on Computer-Aided Design Jones, R. B., Dill, D. L., Burch, J. R. I E E E, COMPUTER SOC PRESS. 1995: 2–6

  View details for Web of Science ID A1995BE64G00001

• Verification of real-time systems by successive over and under approximation 7th Conference on Computer Aided Verification (CAV 95) Dill, D. L., WONGTOI, H. SPRINGER-VERLAG BERLIN. 1995: 409–422

  View details for Web of Science ID A1995BF02S00032

• Improved probabilistic verification by hash compaction IFIP WG 10.5 Advanced Research Working Conference on Correct Hardware Design and Verification Methods (CHARME 95) Stern, U., Dill, D. L. SPRINGER-VERLAG BERLIN. 1995: 206–224

  View details for Web of Science ID A1995BF24P00013

• Automatic verification of the SCI cache coherence protocol IFIP WG 10.5 Advanced Research Working Conference on Correct Hardware Design and Verification Methods (CHARME 95) Stern, U., Dill, D. L. SPRINGER-VERLAG BERLIN. 1995: 21–34

  View details for Web of Science ID A1995BF24P00002

• A THEORY OF TIMED AUTOMATA THEORETICAL COMPUTER SCIENCE Alur, R., Dill, D. L. 1994; 126 (2): 183-235

  View details for Web of Science ID A1994NH36400002

• SYMBOLIC MODEL CHECKING FOR SEQUENTIAL-CIRCUIT VERIFICATION IEEE TRANSACTIONS ON COMPUTER-AIDED DESIGN OF INTEGRATED CIRCUITS AND SYSTEMS Burch, J. R., Clarke, E. M., Long, D. E., McMillan, K. L., Dill, D. L. 1994; 13 (4): 401-424

  View details for Web of Science ID A1994NC80000001

• SELF-TIMED LOGIC USING CURRENT-SENSING COMPLETION DETECTION (CSCD) JOURNAL OF VLSI SIGNAL PROCESSING Dean, M. E., Dill, D. L., Horowitz, M. 1994; 7 (1-2): 7-16

  View details for Web of Science ID A1994NA69100002

• NEW TECHNIQUES FOR EFFICIENT VERIFICATION WITH IMPLICITLY CONJOINED BDDS 31st Design Automation Conference Hu, A. J., York, G., Dill, D. L. ASSOC COMPUTING MACHINERY. 1994: 276–282

  View details for Web of Science ID A1994BC03E00046

• PERFORMANCE-DRIVEN SYNTHESIS OF ASYNCHRONOUS CONTROLLERS 1994 IEEE/ACM International Conference on Computer-Aided Design Yun, K. Y., Lin, B., Dill, D. L., Devadas, S. IEEE COMPUTER SOC. 1994: 550–557

  View details for Web of Science ID A1994BC25F00088

• Conference on Computer-Aided Veri cation, of Lecture Notes in Computer Science edited by Dill, D. L. 1994
• Performance-driven synthesis of asynchronous controllers. Yun, K., Y., Lin, B., Dill, D, L., Devadas, S. 1994
• Symbolic model checking for sequential circuit verification. IEEE Transactions on Computer-Aided Design of Integrated Circuits Burch, Jerry, R., Clarke, Edmund, M., Long, David, E., McMillan, Kenneth, L., Dill, David, L. 1994; 4 (13): 401–424
• Automatic verification of pipelined microprocessor control. Burch, Jerry, R., Dill, David, L. edited by Dill, D. L. 1994
• Self-timed logic using current sensing completion detection (CSCD). Journal of VLSI Signal Processing Dean, M., Dill, David, L., Horowitz, M. 1994; 1–2 (7): 7–16
• THE DESIGN OF A HIGH-PERFORMANCE CACHE CONTROLLER - A CASE-STUDY IN ASYNCHRONOUS SYNTHESIS INTEGRATION-THE VLSI JOURNAL Nowick, S. M., Dean, M. E., Dill, D. L., Horowitz, M. 1993; 15 (3): 241-262

  View details for Web of Science ID A1993MK62900002

• MODEL-CHECKING IN DENSE REAL-TIME INFORMATION AND COMPUTATION Alur, R., Courcoubetis, C., Dill, D. 1993; 104 (1): 2-34

  View details for Web of Science ID A1993LD49200001

• UNIFYING SYNCHRONOUS ASYNCHRONOUS STATE MACHINE SYNTHESIS 1993 IEEE/ACM International Conference on Computer-Aided Design Yun, K. Y., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1993: 255–260

  View details for Web of Science ID A1993BA39Z00044

• EFFICIENT VERIFICATION OF SYMMETRICAL CONCURRENT SYSTEMS 1993 IEEE INTERNATIONAL CONFERENCE ON COMPUTER DESIGN : VLSI IN COMPUTERS AND PROCESSES Ip, C. N., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1993: 230–234

  View details for Web of Science ID A1993BZ24U00041

• AUTOMATIC TECHNOLOGY MAPPING FOR GENERALIZED FUNDAMENTAL-MODE ASYNCHRONOUS DESIGNS 30TH DESIGN AUTOMATION CONF Siegel, P., Demicheli, G., Dill, D. ASSOC COMPUTING MACHINERY. 1993: 61–67

  View details for Web of Science ID A1993BY90U00011

• Efficient verification of bdds using implicitly conjoined invariants. Hu, Alan, J., Dill, David, L. 1993
• Higher-level specification and verification with BDDs. Hu, Alan, J., Dill, David, L., Drexler, Andreas, J., Yang, C., Han 1993
• Automatic technology mapping for generalized fundamental-mode asynchronous designs Siegel, P., Micheli, G. D., Dill, D. 1993
• Automatic technology mapping for generalized fundamental-mode asynchronous designs. Technical Report CSL-TR-93-580, Stanford University Computer Systems Laboratory Siegel, P., Micheli, G. D., Dill, D. 1993
• Model-Checking for Real-Time Systems. Information and Computation Alur, R., Courcoubetis, C., Dill, D. 1993; 1 (104): 2–34
• Practical generalizations of asynchronous state machines. Yun, Kenneth, Y., Dill, David, L., Nowick, Steven, M. 1993
• The design of a high-performance cache controller: a case study in asynchronous synthesis. Integration: the VLSI Journal Nowick, S., M., Dean, M., E., Dill, D., L., Horowitz, M. 1993; 3 (15): 241–262
• Reducing BDD size by exploiting functional dependencies. Hu, Alan, J., Dill, David, L. 1993
• Efficient verification of symmetric concurrent systems. Ip, C. N., Dill, David, L. 1993
• BETTER VERIFICATION THROUGH SYMMETRY IFIP WG10.2 International Conference on Computer Hardware Description Languages and their Applications (CHDL 93) Ip, C. N., Dill, D. L. ELSEVIER SCIENCE BV. 1993: 97–111

  View details for Web of Science ID A1993BZ97A00008

• MODELING HIERARCHICAL COMBINATIONAL-CIRCUITS 1993 IEEE/ACM International Conference on Computer-Aided Design Burch, J. R., Dill, D., Wolf, E., Demicheli, G. I E E E, COMPUTER SOC PRESS. 1993: 612–617

  View details for Web of Science ID A1993BA39Z00101

• FORMAL SPECIFICATION OF ABSTRACT MEMORY MODELS Symposium on Research on Integrated Systems Dill, D. L., Park, S., Nowatzyk, A. G. M I T PRESS. 1993: 38–52

  View details for Web of Science ID A1993BA02Q00003

• SYMBOLIC MODEL CHECKING - 1020 STATES AND BEYOND 5TH SYMP ON LOGIC IN COMPUTER SCIENCE Burch, J. R., Clarke, E. M., McMillan, K. L., Dill, D. L., Hwang, L. J. ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS. 1992: 142–70

  View details for Web of Science ID A1992JA06100002

• CHECKING FOR LANGUAGE INCLUSION USING SIMULATION PREORDERS LECTURE NOTES IN COMPUTER SCIENCE Dill, D. L., Hu, A. J., WONGTOI, H. 1992; 575: 255-265

  View details for Web of Science ID A1992KQ18500026

• ALGORITHMS FOR INTERFACE TIMING VERIFICATION 1992 IEEE INTERNATIONAL CONF ON COMPUTER DESIGN : VLSI IN COMPUTERS & PROCESSORS ( ICCD 92 ) McMillan, K. L., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1992: 48–51

  View details for Web of Science ID A1992BY76C00009

• MINIMIZATION OF TIMED TRANSITION-SYSTEMS 3RD INTERNATIONAL CONF ON CONCURRENCY THEORY Alur, R., Courcoubetis, C., Halbwachs, N., Dill, D., WONGTOI, H. SPRINGER-VERLAG BERLIN. 1992: 340–354

  View details for Web of Science ID A1992BY27A00025

• CHECKING FOR LANGUAGE INCLUSION USING SIMULATION PREORDERS 3RD INTERNATIONAL WORKSHOP ON COMPUTER AIDED VERIFICATION ( CAV 91 ) Dill, D. L., Hu, A. J., WONGTOI, H. SPRINGER-VERLAG BERLIN. 1992: 255–265

  View details for Web of Science ID A1992BX63T00026

• PRACTICAL ASYNCHRONOUS CONTROLLER-DESIGN 1992 IEEE INTERNATIONAL CONF ON COMPUTER DESIGN : VLSI IN COMPUTERS & PROCESSORS ( ICCD 92 ) Nowick, S. M., Yun, K. Y., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1992: 341–345

  View details for Web of Science ID A1992BY76C00067

• SYNTHESIS OF 3D ASYNCHRONOUS STATE MACHINES 1992 IEEE INTERNATIONAL CONF ON COMPUTER DESIGN : VLSI IN COMPUTERS & PROCESSORS ( ICCD 92 ) Yun, K. Y., Dill, D. L., Nowick, S. M. I E E E, COMPUTER SOC PRESS. 1992: 346–350

  View details for Web of Science ID A1992BY76C00068

• AN IMPLEMENTATION OF 3 ALGORITHMS FOR TIMING VERIFICATION BASED ON AUTOMATA EMPTINESS CONF ON REAL-TIME SYSTEMS SYMP Alur, R., Courcoubetis, C., Dill, D., Halbwachs, N., WONGTOI, H. I E E E, COMPUTER SOC PRESS. 1992: 157–166

  View details for Web of Science ID A1992BY08D00015

• Synthesis of 3D asynchronous state machines. Yun, Kenneth, Y., Dill, David, L. 1992
• Protocol verification as a hardware design aid. Dill, David, L., Drexler, Andreas, J., Hu, Alan, J., Yang, C., Han 1992
• Practical asynchronous controller design. Nowick, Steven, M., Yun, K., Dill, David, L. 1992
• Algorithms for interface timing verification. McMillan, K., Dill, David, L. 1992
• Specification and automatic verification of self-timed queues Formal Methods in Systems Design Dill, David, L., Nowick, Steven, M., Sproull, Robert, F. 1992; 1 (1): 29–62
• Automatic synthesis of 3D asynchronous state machines. Yun, Kenneth, Y., Dill, David, L. 1992
• The theory of timed automata. In Real-Time: Theory in Practice, volume 600 of Lecture Notes in Computer Science Alur, R., Dill, David, L. REX Workshop, Mook, The Netherlands. 1992: 45–73
• Practical generalizations of asynchronous state machines. Technical Report CSL-TR-92-544, Computer Systems Laboratory, Stanford University Yun, Kenneth, Y., Dill, David, L., Nowick, Steven, M. 1992
• Formal Verification of Cache Systems using Refinement Relations. Formal Methods in Systems Design Loewenstein, P., Dill, D. 1992; 4 (1): 355–383
• Verification with real-time COSPAN. Courcoubetis, C., Dill, D., Chatzaki, M., Tzounakis, P. 1992
• An Implementation of Three Algorithms for Timing Veri cation Based on Automata Emptiness. Alur, R., Courcoubetis, C., Dill, D., Halbwachs, N., Wong-Toi, H. 1992
• Verifying automata specifications of probabilistic real-time systems. In Real-Time: Theory in Practice, volume 600 of Lecture Notes in Computer Science Alur, R., Courcoubetis, C., Dill, David, L. REX Workshop, Mook, The Netherlands. 1992: 28–44
• Symbolic model checking: 1020 states and beyond. Information and Computation Burch, J., R., Clarke, E., M., McMillan, K., L., Dill, D., L., Hwang, L., J. 1992; 2 (98): 142–170
• THE THEORY OF TIMED AUTOMATA REX WORKSHOP ON REAL-TIME : THEORY IN PRACTICE Alur, R., Dill, D. SPRINGER VERLAG. 1992: 45–73

  View details for Web of Science ID A1992LE88200004

• VERIFYING AUTOMATA SPECIFICATIONS OF PROBABILISTIC REAL-TIME SYSTEMS REX WORKSHOP ON REAL-TIME : THEORY IN PRACTICE Alur, R., Courcoubetis, C., Dill, D. SPRINGER VERLAG. 1992: 28–44

  View details for Web of Science ID A1992LE88200003

• MINIMIZATION OF TIMED TRANSITION-SYSTEMS LECTURE NOTES IN COMPUTER SCIENCE Alur, R., Courcoubetis, C., Halbwachs, N., Dill, D., WONGTOI, H. 1992; 630: 340-354

  View details for Web of Science ID A1992LF69300025

• MODEL-CHECKING FOR PROBABILISTIC REAL-TIME SYSTEMS LECTURE NOTES IN COMPUTER SCIENCE Alur, R., Courcoubetis, C., Dill, D. 1991; 510: 115-126

  View details for Web of Science ID A1991GA06500008

• MODEL-CHECKING FOR PROBABILISTIC REAL-TIME SYSTEMS 18TH INTERNATIONAL COLLOQUIUM ON AUTOMATA, LANGUAGES AND PROGRAMMING ( ICALP 91 ) Alur, R., Courcoubetis, C., Dill, D. SPRINGER-VERLAG BERLIN. 1991: 115–126

  View details for Web of Science ID A1991BT82D00008

• SYNTHESIS OF ASYNCHRONOUS STATE MACHINES USING A LOCAL CLOCK INTERNATIONAL CONF ON COMPUTER DESIGN : VLSI IN COMPUTERS AND PROCESSORS Nowick, S. M., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1991: 192–197

  View details for Web of Science ID A1991BU43M00038

• Synthesis of asynchronous state machines using a local clock. Nowick, Steven, M., Dill, David, L. 1991
• Efficient self-timing with level-encoded two-phase dual rail (LEDR). Dean, Mark, E., Williams, Ted, E., Dill, David, L. 1991
• Automatic synthesis of locally-clocked asynchronous state machines. Nowick, Steven, M., Dill, David, L. 1991
• SELF-TIMED LOGIC USING CURRENT-SENSING COMPLETION DETECTION (CSCD) INTERNATIONAL CONF ON COMPUTER DESIGN : VLSI IN COMPUTERS AND PROCESSORS Dean, M. E., Dill, D. L., Horowitz, M. I E E E, COMPUTER SOC PRESS. 1991: 187–191

  View details for Web of Science ID A1991BU43M00037

• SYNTHESIZING PROCESSES AND SCHEDULERS FROM TEMPORAL SPECIFICATIONS 2ND INTERNATIONAL CONF ON COMPUTER-AIDED VERIFICATION ( CAV 90 ) WONGTOI, H., Dill, D. L. SPRINGER. 1991: 272–281

  View details for Web of Science ID A1991LE71400029

• COMPLETE TRACE STRUCTURES WORKSHOP ON HARDWARE SPECIFICATION, VERIFICATION AND SYNTHESIS : MATHEMATICAL ASPECTS Dill, D. L. SPRINGER-VERLAG BERLIN. 1990: 224–243

  View details for Web of Science ID A1990BQ26K00012

• TIMING ASSUMPTIONS AND VERIFICATION OF FINITE-STATE CONCURRENT SYSTEMS LECTURE NOTES IN COMPUTER SCIENCE Dill, D. L. 1990; 407: 197-212

  View details for Web of Science ID A1990CU37800017

• COMPLETE TRACE STRUCTURES LECTURE NOTES IN COMPUTER SCIENCE Dill, D. L. 1990; 408: 224-243

  View details for Web of Science ID A1990CU37400012

• AUTOMATA FOR MODELING REAL-TIME SYSTEMS 17TH INTERNATIONAL COLLOQUIUM ON AUTOMATA, LANGUAGES AND PROGRAMMING ( ICALP 90 ) Alur, R., Dill, D. SPRINGER-VERLAG. 1990: 322–335

  View details for Web of Science ID A1990BR56W00026

• Symbolic model checking: 10 states and beyond. Burch, J., R., Clarke, E., M., McMillan, K., L., Dill, D., L., Hwang, J. 1990
• Sequential circuit verification using symbolic model-checking. Burch, J., R., Clarke, E., M., Dill, D., L., McMillan, K., L. 1990
• Specification and automatic verification of self-timed queues Formal Veri cation of Hardware Design Dill, D. L., Nowick, S. M., Sproull, R. F. edited by Yoeli, M. IEEE Computer Society Press. 1990: 225–248
• Model-checking for real-time systems. Alur, R., Courcoubetis, C., Dill, D. 1990
• Automatic verification of sequential circuits using temporal logic Formal Verification of Hardware Design. Browne, M. C., Clarke, E. M., Dill, D. L., Mishra, B. edited by Yoeli, M. IEEE Computer Society Press. 1990: 166–175
• Automatic verification Synchronization Design for Digital Systems Nowick, S. M., Dill, D. L. edited by Meng, T. H. Kluwer Academic Publishers. 1990: 147–172
• Automatic verification of asynchronous circuits using temporal logic. Formal Verification of Hardware Design, Reprint of a paper in IEE proceedings, Pt. E. Dill, David, L., Clarke, Edmund, M. edited by Yoeli, M. IEEE Computer Society Press. 1990: 176–183
• AUTOMATA FOR MODELING REAL-TIME SYSTEMS LECTURE NOTES IN COMPUTER SCIENCE Alur, R., Dill, D. 1990; 443: 322-335

  View details for Web of Science ID A1990DX76000026

• TIMING ASSUMPTIONS AND VERIFICATION OF FINITE-STATE CONCURRENT SYSTEMS INTERNATIONAL WORKSHOP ON AUTOMATIC VERIFICATION METHODS FOR FINITE STATE SYSTEMS Dill, D. L. SPRINGER-VERLAG BERLIN. 1990: 197–212

  View details for Web of Science ID A1990BQ26L00017

• Complete trace structures In Hardware Speci cation, Veri cation and Synthesis: Mathematical Aspects, volume 408 of Lecture Notes in Computer Science Dill, D. L. 1989: 224–243
• PRACTICALITY OF STATE-MACHINE VERIFICATION OF SPEED-INDEPENDENT CIRCUITS 1989 IEEE INTERNATIONAL CONF ON COMPUTER-AIDED DESIGN : A CONF FOR THE EE CAD PROFESSIONAL ( ICCAD-89 ) Nowick, S. M., Dill, D. L. I E E E, COMPUTER SOC PRESS. 1989: 266–269

  View details for Web of Science ID A1989BP87R00059

• AUTOMATIC VERIFICATION OF SPEED-INDEPENDENT CIRCUITS WITH PETRI NET SPECIFICATIONS 1989 IEEE INTERNATIONAL CONF ON COMPUTER DESIGN : VLSI IN COMPUTERS AND PROCESSORS Dill, D. L., Nowick, S. M., SPROULL, R. F. I E E E. 1989: 212–216

  View details for Web of Science ID A1989BP71U00041

• Practicality of state-machine verification of speed-independent circuits. Nowick, Steven, M., Dill, David, L. 1989
• Automatic verification of speed-independent circuits with Petri net specifications. Dill, David, L., Nowick, Steven, M., Sproull, Robert, F. 1989
• Trace Theory for Automatic Hierarchical Veri cation of Speed-independent Circuits edited by Dill, D. L. MIT Press. 1989
• Specification and automatic verification of self-timed queues. Technical Report CSL-TR-89-387, Computer Systems Laboratory, Stanford University, This was reprinted in the IEEE tutorial: Formal Verification of Hardware Design, by Michael Yoeli Dill, David, L., Nowick, Steven, M., Sproull, Robert, F. 1989
• Trace theory for automatic hierarchical verification of speed-independent circuits. Dill, David, L. 1988
• AUTOMATIC VERIFICATION OF SEQUENTIAL-CIRCUITS USING TEMPORAL LOGIC IEEE TRANSACTIONS ON COMPUTERS Browne, M. C., Clarke, E. M., Dill, D. L., Mishra, B. 1986; 35 (12): 1035-1044

  View details for Web of Science ID A1986E848200003

• AUTOMATIC VERIFICATION OF ASYNCHRONOUS CIRCUITS USING TEMPORAL LOGIC IEE PROCEEDINGS-E COMPUTERS AND DIGITAL TECHNIQUES Dill, D. L., Clarke, E. M. 1986; 133 (5): 276-282

  View details for Web of Science ID A1986E282200005

• Automatic verification of sequential circuits using temporal logic. IEEE Transactions on Computers, This was reprinted in the IEEE tutorial: Formal Veri cation of Hardware Design, by Michael Yoeli Browne, Michael, C., Clarke, Edmund, M., Dill, David, L., Mishra, B. 1986; 12 (C-35): 1035–1044
• Automatic circuit verification using temporal logic: Two new examples. Browne, Michael, C., Clarke, Edmund, M., Dill, David, L. 1986
• Automatic verification of asynchronous circuits using temporal logic Dill, David, L., Clark, Edmund, M. 1986
• Automatic verification of asynchronous circuits using temporal logic. Technical Report CMU-CS-85-125, Department of Computer Science, Carnegie-Mellon University Dill, David, L., Clarke, Edmund, M. 1985
• Automatic verification of sequential circuits using temporal logic. Browne, Michael, C., Clarke, Edmund, M., Dill, David, L., Mishra, B. 1985
• Checking the correctness of sequential circuits. Browne, Michael, C., Clarke, Edmund, M., Dill, David, L. 1985
• Automatic verification of asynchronous circuits using temporal logic. Dill, David, L., Clarke, Edmund, M. 1985
• Automatic verification of sequential circuits using temporal logic. Technical Report CMU-CS-85-100, Department of Computer Science, Carnegie-Mellon University Browne, Michael, C., Clarke, Edmund, M., Dill, David, L., Mishra, B. 1984