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4,613 results on '"Reed, Robert A."'

1. Learning-Based Shielding for Safe Autonomy under Unknown Dynamics

Author

Reed, Robert and Lahijanian, Morteza

Subjects
Electrical Engineering and Systems Science - Systems and Control, Computer Science - Machine Learning
Abstract

Shielding is a common method used to guarantee the safety of a system under a black-box controller, such as a neural network controller from deep reinforcement learning (DRL), with simpler, verified controllers. Existing shielding methods rely on formal verification through Markov Decision Processes (MDPs), assuming either known or finite-state models, which limits their applicability to DRL settings with unknown, continuous-state systems. This paper addresses these limitations by proposing a data-driven shielding methodology that guarantees safety for unknown systems under black-box controllers. The approach leverages Deep Kernel Learning to model the systems' one-step evolution with uncertainty quantification and constructs a finite-state abstraction as an Interval MDP (IMDP). By focusing on safety properties expressed in safe linear temporal logic (safe LTL), we develop an algorithm that computes the maximally permissive set of safe policies on the IMDP, ensuring avoidance of unsafe states. The algorithms soundness and computational complexity are demonstrated through theoretical proofs and experiments on nonlinear systems, including a high-dimensional autonomous spacecraft scenario., Comment: 8 pages, 3 figures

Published
2024

2. Error Bounds For Gaussian Process Regression Under Bounded Support Noise With Applications To Safety Certification

Author

Reed, Robert, Laurenti, Luca, and Lahijanian, Morteza

Subjects
Computer Science - Machine Learning, Statistics - Machine Learning
Abstract

Gaussian Process Regression (GPR) is a powerful and elegant method for learning complex functions from noisy data with a wide range of applications, including in safety-critical domains. Such applications have two key features: (i) they require rigorous error quantification, and (ii) the noise is often bounded and non-Gaussian due to, e.g., physical constraints. While error bounds for applying GPR in the presence of non-Gaussian noise exist, they tend to be overly restrictive and conservative in practice. In this paper, we provide novel error bounds for GPR under bounded support noise. Specifically, by relying on concentration inequalities and assuming that the latent function has low complexity in the reproducing kernel Hilbert space (RKHS) corresponding to the GP kernel, we derive both probabilistic and deterministic bounds on the error of the GPR. We show that these errors are substantially tighter than existing state-of-the-art bounds and are particularly well-suited for GPR with neural network kernels, i.e., Deep Kernel Learning (DKL). Furthermore, motivated by applications in safety-critical domains, we illustrate how these bounds can be combined with stochastic barrier functions to successfully quantify the safety probability of an unknown dynamical system from finite data. We validate the efficacy of our approach through several benchmarks and comparisons against existing bounds. The results show that our bounds are consistently smaller, and that DKLs can produce error bounds tighter than sample noise, significantly improving the safety probability of control systems., Comment: 11 pages, 5 figures, 6 tables

Published
2024

3. Shielded Deep Reinforcement Learning for Complex Spacecraft Tasking

Author

Reed, Robert, Schaub, Hanspeter, and Lahijanian, Morteza

Subjects
Computer Science - Machine Learning
Abstract

Autonomous spacecraft control via Shielded Deep Reinforcement Learning (SDRL) has become a rapidly growing research area. However, the construction of shields and the definition of tasking remains informal, resulting in policies with no guarantees on safety and ambiguous goals for the RL agent. In this paper, we first explore the use of formal languages, namely Linear Temporal Logic (LTL), to formalize spacecraft tasks and safety requirements. We then define a manner in which to construct a reward function from a co-safe LTL specification automatically for effective training in SDRL framework. We also investigate methods for constructing a shield from a safe LTL specification for spacecraft applications and propose three designs that provide probabilistic guarantees. We show how these shields interact with different policies and the flexibility of the reward structure through several experiments., Comment: 9 pages, 2 figures, 2 tables, ACC 2024

Published
2024

4. Promises of Deep Kernel Learning for Control Synthesis

Author

Reed, Robert, Laurenti, Luca, and Lahijanian, Morteza

Subjects
Electrical Engineering and Systems Science - Systems and Control, Computer Science - Machine Learning
Abstract

Deep Kernel Learning (DKL) combines the representational power of neural networks with the uncertainty quantification of Gaussian Processes. Hence, it is potentially a promising tool to learn and control complex dynamical systems. In this work, we develop a scalable abstraction-based framework that enables the use of DKL for control synthesis of stochastic dynamical systems against complex specifications. Specifically, we consider temporal logic specifications and create an end-to-end framework that uses DKL to learn an unknown system from data and formally abstracts the DKL model into an Interval Markov Decision Process (IMDP) to perform control synthesis with correctness guarantees. Furthermore, we identify a deep architecture that enables accurate learning and efficient abstraction computation. The effectiveness of our approach is illustrated on various benchmarks, including a 5-D nonlinear stochastic system, showing how control synthesis with DKL can substantially outperform state-of-the-art competitive methods., Comment: 9 pages, 4 figures, 3 tables

Published
2023

5. Phyllosphere microbial associations improve plant reproductive success

Author

Mehlferber, Elijah C, Debray, Reena, Conover, Asa E, Sherman, Julia K, Kaulbach, Griffin, Reed, Robert, McCue, Kent F, Ferrel, Jon E, Khanna, Rajnish, and Koskella, Britt

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Ecology, Microbiology, Plant Biology, Crop and Pasture Production, Climate Action, biostimulants, greenhouse growth, phyllosphere microbiome, plant probiotic, Solanum lycopersicum, synthetic microbiome, tomato yield, Crop and pasture production, Plant biology
Abstract

The above-ground (phyllosphere) plant microbiome is increasingly recognized as an important component of plant health. We hypothesized that phyllosphere bacterial recruitment may be disrupted in a greenhouse setting, and that adding a bacterial amendment would therefore benefit the health and growth of host plants. Using a newly developed synthetic phyllosphere bacterial microbiome for tomato (Solanum lycopersicum), we tested this hypothesis across multiple trials by manipulating microbial inoculation of leaves and measuring subsequent plant growth and reproductive success, comparing results from plants grown in both greenhouse and field settings. We confirmed that greenhouse-grown plants have a relatively depauperate phyllosphere bacterial microbiome, which both makes them an ideal system for testing the impact of phyllosphere communities on plant health and important targets for microbial amendments as we move towards increased agricultural sustainability. We find that the addition of the synthetic microbial community early in greenhouse growth leads to an increase in fruit production in this setting, implicating the phyllosphere microbiome as a key component of plant fitness and emphasizing the role that these bacterial microbiomes likely play in the ecology and evolution of plant communities.

Published
2023

6. Rare genetic variants explain missing heritability in smoking.

Author

Jang, Seon-Kyeong, Evans, Luke, Fialkowski, Allison, Arnett, Donna K, Ashley-Koch, Allison E, Barnes, Kathleen C, Becker, Diane M, Bis, Joshua C, Blangero, John, Bleecker, Eugene R, Boorgula, Meher Preethi, Bowden, Donald W, Brody, Jennifer A, Cade, Brian E, Jenkins, Brenda W Campbell, Carson, April P, Chavan, Sameer, Cupples, L Adrienne, Custer, Brian, Damrauer, Scott M, David, Sean P, de Andrade, Mariza, Dinardo, Carla L, Fingerlin, Tasha E, Fornage, Myriam, Freedman, Barry I, Garrett, Melanie E, Gharib, Sina A, Glahn, David C, Haessler, Jeffrey, Heckbert, Susan R, Hokanson, John E, Hou, Lifang, Hwang, Shih-Jen, Hyman, Matthew C, Judy, Renae, Justice, Anne E, Kaplan, Robert C, Kardia, Sharon LR, Kelly, Shannon, Kim, Wonji, Kooperberg, Charles, Levy, Daniel, Lloyd-Jones, Donald M, Loos, Ruth JF, Manichaikul, Ani W, Gladwin, Mark T, Martin, Lisa Warsinger, Nouraie, Mehdi, Melander, Olle, Meyers, Deborah A, Montgomery, Courtney G, North, Kari E, Oelsner, Elizabeth C, Palmer, Nicholette D, Payton, Marinelle, Peljto, Anna L, Peyser, Patricia A, Preuss, Michael, Psaty, Bruce M, Qiao, Dandi, Rader, Daniel J, Rafaels, Nicholas, Redline, Susan, Reed, Robert M, Reiner, Alexander P, Rich, Stephen S, Rotter, Jerome I, Schwartz, David A, Shadyab, Aladdin H, Silverman, Edwin K, Smith, Nicholas L, Smith, J Gustav, Smith, Albert V, Smith, Jennifer A, Tang, Weihong, Taylor, Kent D, Telen, Marilyn J, Vasan, Ramachandran S, Gordeuk, Victor R, Wang, Zhe, Wiggins, Kerri L, Yanek, Lisa R, Yang, Ivana V, Young, Kendra A, Young, Kristin L, Zhang, Yingze, Liu, Dajiang J, Keller, Matthew C, and Vrieze, Scott

Subjects
Smoking, Gene Frequency, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Tobacco, Genetics, Tobacco Smoke and Health, Human Genome, Cancer
Abstract

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

Published
2022

9. Response of a Commercial 0.25 um Thin-Film Silicon-on-Sapphire CMOS Technology to Total Ionizing Dose

Author

King, Michael P., Gong, Datao, Liu, Chonghan, Liu, Tiankuan, Xiang, Annie C., Ye, Jinbo, Schrimpf, Ronald D., Reed, Robert A., Alles, Michael L., and Fleetwood, Daniel M.

Subjects
Physics - Instrumentation and Detectors
Abstract

The radiation response of a 0.25 um silicon-on-sapphire CMOS technology is characterized at the transistor and circuit levels utilizing both standard and enclosed layout devices. Device-level characterization showed threshold voltage change of less than 170 mV and leakage current change of less than 1 nA for individual nMOSFET and pMOSFET devices at a total dose of 100 krad(SiO2). The increase in power supply current at the circuit level was less than 5%, consistent with the small change in off-state transistor leakage current. The technology exhibits good characteristics for use in the electronics of the ATLAS experiment at the Large Hadron Collider., Comment: 5 pages, 5 figures

Published
2022
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12. A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K, Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P, Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Dan, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J. F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A, Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L, Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C, Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S, Pleiness, Jacob, Pollin, Toni, Post, Wendy, Becker, Julia Powers, Boorgula, Meher Preethi, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D. C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Hui-Heng Sheu, Wayne, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent D., Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T, Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Lindstrom, Sara, Wang, Lu, Smith, Erin N., Gordon, William, van Hylckama Vlieg, Astrid, Brody, Jennifer A., Pattee, Jack W., Haessler, Jeffrey, Brumpton, Ben M., Chasman, Daniel I., Suchon, Pierre, Chen, Ming-Huei, Turman, Constance, Germain, Marine, Wiggins, Kerri L., MacDonald, James, Braekkan, Sigrid K., Armasu, Sebastian M., Pankratz, Nathan, Jackson, Rabecca D., Nielsen, Jonas B., Giulianini, Franco, Puurunen, Marja K., Ibrahim, Manal, Heckbert, Susan R., Bammler, Theo K., Frazer, Kelly A., McCauley, Bryan M., Taylor, Kent, Pankow, James S., Reiner, Alexander P., Gabrielsen, Maiken E., Deleuze, Jean-François, O'Donnell, Chris J., Kim, Jihye, McKnight, Barbara, Kraft, Peter, Hansen, John-Bjarne, Rosendaal, Frits R., Heit, John A., Psaty, Bruce M., Tang, Weihong, Hveem, Kristian, Ridker, Paul M., Morange, Pierre-Emmanuel, Johnson, Andrew D., Kabrhel, Christopher, AlexandreTrégouët, David, Smith, Nicholas L., de Vries, Paul S., Reventun, Paula, Brown, Michael R., Heath, Adam S., Huffman, Jennifer E., Le, Ngoc-Quynh, Bebo, Allison, Temprano-Sagrera, Gerard, Raffield, Laura M., Ozel, Ayse Bilge, Thibord, Florian, Lewis, Joshua P., Rodriguez, Benjamin A. T., Polasek, Ozren, Yanek, Lisa R., Carrasquilla, German D., Marioni, Riccardo E., Kleber, Marcus E., Trégouët, David-Alexandre, Yao, Jie, Li-Gao, Ruifang, Joshi, Peter K., Trompet, Stella, Martinez-Perez, Angel, Ghanbari, Mohsen, Howard, Tom E., Reiner, Alex P., Arvanitis, Marios, Ryan, Kathleen A., Bartz, Traci M., Rudan, Igor, Faraday, Nauder, Linneberg, Allan, Davies, Gail, Delgado, Graciela E., Klaric, Lucija, Noordam, Raymond, van Rooij, Frank, Curran, Joanne E., Wheeler, Marsha M., Osburn, William O., O'Connell, Jeffrey R., Beswick, Andrew, Kolcic, Ivana, Souto, Juan Carlos, Becker, Lewis C., Hansen, Torben, Doyle, Margaret F., Harris, Sarah E., Moissl, Angela P., Rich, Stephen S., Campbell, Harry, Stott, David J., Soria, Jose Manuel, de Maat, Moniek P. M., Brody, Lawrence C., Auer, Paul L., Ben-Shlomo, Yoav, Hayward, Caroline, Mathias, Rasika A., Kilpeläinen, Tuomas O., Lange, Leslie A., Cox, Simon R., März, Winfried, Rotter, Jerome I., Mook-Kanamori, Dennis O., Wilson, James F., van der Harst, Pim, Jukema, J. Wouter, Ikram, M. Arfan, Desch, Karl C., Sabater-Lleal, Maria, Lowenstein, Charles J., and Morrison, Alanna C.

Published
2024
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15. Multiethnic genome-wide and HLA association study of total serum IgE level

Author

Daya, Michelle, Cox, Corey, Acevedo, Nathalie, Boorgula, Meher P, Campbell, Monica, Chavan, Sameer, Cho, Michael H, David, Gloria L, Kachroo, Priyadarshini, Lasky-Su, Jessica, Li, Xingnan, McHugh, Caitlin P, Qiao, Dandi, Rafaels, Nicholas, Beck, Lisa A, Bleecker, Eugene R, Caraballo, Luis, Cupples, Adrienne L, Figueiredo, Camila A, Gallo, Richard L, Hanifin, Jon, Hansel, Nadia N, Hata, Tissa R, Hersh, Craig P, Knight-Madden, Jennifer, Leung, Donald YM, Guttman-Yassky, Emma, Meyers, Deborah A, O’Connor, George, Ober, Carole, Ong, Peck Y, Ortega, Victor E, Paller, Amy S, Putcha, Nirupama, Reed, Robert M, Schneider, Lynda C, Silverman, Edwin K, Slifka, Mark K, Spergel, Jonathan M, Vasan, Ramachandran S, Viaud-Martinez, Karine A, Watson, Harold, Weiss, Scott T, Consortium, NHLBI Trans-Omics for Precision Medicine, Ruczinski, Ingo, Beaty, Terri H, Mathias, Rasika A, and Barnes, Kathleen C

Subjects
Clinical Research, Genetics, Lung, Asthma, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Inflammatory and immune system, Good Health and Well Being, Adolescent, Adult, Aged, Child, Child, Preschool, Dermatitis, Atopic, Ethnicity, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, HLA-A2 Antigen, HLA-DQ beta-Chains, Humans, Immunoglobulin E, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), United States, Whole Genome Sequencing, Young Adult, Total serum IgE, human leukocyte antigen, genome-wide association study, atopic dermatitis, asthma, multiethnic, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Immunology, Allergy
Abstract

BackgroundTotal serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.ObjectiveWe aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901).MethodsWe performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data.ResultsWe identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8).ConclusionWe performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.

Published
2021

16. Epigenetic marker of telomeric age is associated with exacerbations and hospitalizations in chronic obstructive pulmonary disease

Author

Hernández Cordero, Ana I, Yang, Chen Xi, Li, Xuan, Milne, Stephen, Chen, Virginia, Hollander, Zsuzsanna, Ng, Raymond, Criner, Gerard J, Woodruff, Prescott G, Lazarus, Stephen C, Connett, John E, Han, MeiLan K, Martinez, Fernando J, Reed, Robert M, Man, SF Paul, Leung, Janice M, and Sin, Don D

Subjects
Chronic Obstructive Pulmonary Disease, Lung, Genetics, Clinical Research, Prevention, Respiratory, Adult, Aged, Anti-Bacterial Agents, Azithromycin, Biomarkers, DNA Methylation, Disease Progression, Female, Follow-Up Studies, Hospitalization, Humans, Incidence, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Quality of Life, Retrospective Studies, Surveys and Questionnaires, Telomere, Time Factors, United States, COPD, Telomeres, AECOPD, Epigenetics, DNA methylation, Cardiorespiratory Medicine and Haematology, Clinical Sciences, Respiratory System
Abstract

BackgroundChronic obstructive pulmonary disease (COPD) is an age-related condition that has been associated with early telomere attrition; the clinical implications of telomere shortening in COPD are not well known. In this study we aimed to determine the relationship of the epigenetic regulation of telomeric length in peripheral blood with the risk of exacerbations and hospitalization in patients with COPD.MethodsBlood DNA methylation profiles were obtained from 292 patients with COPD enrolled in the placebo arm of the Macrolide Azithromycin to Prevent Rapid Worsening of Symptoms Associated with Chronic Obstructive Pulmonary Disease (MACRO) Study and who were followed for 1-year. We calculated telomere length based on DNA methylation markers (DNAmTL) and related this biomarker to the risk of exacerbation and hospitalization and health status (St. George Respiratory Questionnaire [SGRQ]) score over time using a Cox proportional hazards model. We also used linear models to investigate the associations of DNAmTL with the rates of exacerbation and hospitalization (adjusted for chronological age, lung function, race, sex, smoking, body mass index and cell composition).ResultsParticipants with short DNAmTL demonstrated increased risk of exacerbation (P = 0.02) and hospitalization (P = 0.03) compared to those with longer DNAmTL. DNAmTL age acceleration was associated with higher rates of exacerbation (P = 1.35 × 10-04) and hospitalization (P = 5.21 × 10-03) and poor health status (lower SGRQ scores) independent of chronological age (P = 0.03).ConclusionTelomeric age based on blood DNA methylation is associated with COPD exacerbation and hospitalization and thus a promising biomarker for poor outcomes in COPD.

Published
2021

18. Epigenome-wide DNA methylation association study of circulating IgE levels identifies novel targets for asthma

Author

Abe, Namiko, Abecasis, Gonçalo, Aguet, Francois, Albert, Christine, Almasy, Laura, Alonso, Alvaro, Ament, Seth, Anderson, Peter, Anugu, Pramod, Applebaum-Bowden, Deborah, Ardlie, Kristin, Arking, Dan, Arnett, Donna K., Ashley-Koch, Allison, Aslibekyan, Stella, Assimes, Tim, Auer, Paul, Avramopoulos, Dimitrios, Ayas, Najib, Balasubramanian, Adithya, Barnard, John, Barnes, Kathleen, Barr, R. Graham, Barron-Casella, Emily, Barwick, Lucas, Beaty, Terri, Beck, Gerald, Becker, Diane, Becker, Lewis, Beer, Rebecca, Beitelshees, Amber, Benjamin, Emelia, Benos, Takis, Bezerra, Marcos, Bielak, Larry, Bis, Joshua, Blackwell, Thomas, Blangero, John, Blue, Nathan, Boerwinkle, Eric, Bowden, Donald W., Bowler, Russell, Brody, Jennifer, Broeckel, Ulrich, Broome, Jai, Brown, Deborah, Bunting, Karen, Burchard, Esteban, Bustamante, Carlos, Buth, Erin, Cade, Brian, Cardwell, Jonathan, Carey, Vincent, Carrier, Julie, Carson, April P., Carty, Cara, Casaburi, Richard, Casas Romero, Juan P., Casella, James, Castaldi, Peter, Chaffin, Mark, Chang, Christy, Chang, Yi-Cheng, Chasman, Daniel, Chavan, Sameer, Chen, Bo-Juen, Chen, Wei-Min, Ida Chen, Yii-Der, Cho, Michael, Choi, Seung Hoan, Chuang, Lee-Ming, Chung, Mina, Chung, Ren-Hua, Clish, Clary, Comhair, Suzy, Conomos, Matthew, Cornell, Elaine, Correa, Adolfo, Crandall, Carolyn, Crapo, James, Cupples, L. Adrienne, Curran, Joanne, Curtis, Jeffrey, Custer, Brian, Damcott, Coleen, Darbar, Dawood, David, Sean, Davis, Colleen, Daya, Michelle, de Andrade, Mariza, de las Fuentes, Lisa, de Vries, Paul, DeBaun, Michael, Deka, Ranjan, DeMeo, Dawn, Devine, Scott, Dinh, Huyen, Doddapaneni, Harsha, Duan, Qing, Dugan-Perez, Shannon, Duggirala, Ravi, Durda, Jon Peter, Dutcher, Susan K., Eaton, Charles, Ekunwe, Lynette, El Boueiz, Adel, Ellinor, Patrick, Emery, Leslie, Erzurum, Serpil, Farber, Charles, Farek, Jesse, Fingerlin, Tasha, Flickinger, Matthew, Fornage, Myriam, Franceschini, Nora, Frazar, Chris, Fu, Mao, Fullerton, Stephanie M., Fulton, Lucinda, Gabriel, Stacey, Gan, Weiniu, Gao, Shanshan, Gao, Yan, Gass, Margery, Geiger, Heather, Gelb, Bruce, Geraci, Mark, Germer, Soren, Gerszten, Robert, Ghosh, Auyon, Gibbs, Richard, Gignoux, Chris, Gladwin, Mark, Glahn, David, Gogarten, Stephanie, Gong, Da-Wei, Goring, Harald, Graw, Sharon, Gray, Kathryn J., Grine, Daniel, Gross, Colin, Gu, C. Charles, Guan, Yue, Guo, Xiuqing, Gupta, Namrata, Haessler, Jeff, Hall, Michael, Han, Yi, Hanly, Patrick, Harris, Daniel, Hawley, Nicola L., He, Jiang, Heavner, Ben, Heckbert, Susan, Hernandez, Ryan, Herrington, David, Hersh, Craig, Hidalgo, Bertha, Hixson, James, Hobbs, Brian, Hokanson, John, Hong, Elliott, Hoth, Karin, Hsiung, Chao (Agnes), Hu, Jianhong, Hung, Yi-Jen, Huston, Haley, Hwu, Chii Min, Irvin, Marguerite Ryan, Jackson, Rebecca, Jain, Deepti, Jaquish, Cashell, Johnsen, Jill, Johnson, Andrew, Johnson, Craig, Johnston, Rich, Jones, Kimberly, Kang, Hyun Min, Kaplan, Robert, Kardia, Sharon, Kelly, Shannon, Kenny, Eimear, Kessler, Michael, Khan, Alyna, Khan, Ziad, Kim, Wonji, Kimoff, John, Kinney, Greg, Konkle, Barbara, Kooperberg, Charles, Kramer, Holly, Lange, Christoph, Lange, Ethan, Lange, Leslie, Laurie, Cathy, Laurie, Cecelia, LeBoff, Meryl, Lee, Jiwon, Lee, Sandra, Lee, Wen-Jane, LeFaive, Jonathon, Levine, David, Levy, Daniel, Lewis, Joshua, Li, Xiaohui, Li, Yun, Lin, Henry, Lin, Honghuang, Lin, Xihong, Liu, Simin, Liu, Yongmei, Liu, Yu, Loos, Ruth J.F., Lubitz, Steven, Lunetta, Kathryn, Luo, James, Magalang, Ulysses, Mahaney, Michael, Make, Barry, Manichaikul, Ani, Manning, Alisa, Manson, JoAnn, Martin, Lisa, Marton, Melissa, Mathai, Susan, Mathias, Rasika, May, Susanne, McArdle, Patrick, McDonald, Merry-Lynn, McFarland, Sean, McGarvey, Stephen, McGoldrick, Daniel, McHugh, Caitlin, McNeil, Becky, Mei, Hao, Meigs, James, Menon, Vipin, Mestroni, Luisa, Metcalf, Ginger, Meyers, Deborah A., Mignot, Emmanuel, Mikulla, Julie, Min, Nancy, Minear, Mollie, Minster, Ryan L., Mitchell, Braxton D., Moll, Matt, Momin, Zeineen, Montasser, May E., Montgomery, Courtney, Muzny, Donna, Mychaleckyj, Josyf C., Nadkarni, Girish, Naik, Rakhi, Naseri, Take, Natarajan, Pradeep, Nekhai, Sergei, Nelson, Sarah C., Neltner, Bonnie, Nessner, Caitlin, Nickerson, Deborah, Nkechinyere, Osuji, North, Kari, O'Connell, Jeff, O'Connor, Tim, Ochs-Balcom, Heather, Okwuonu, Geoffrey, Pack, Allan, Paik, David T., Palmer, Nicholette, Pankow, James, Papanicolaou, George, Parker, Cora, Peloso, Gina, Peralta, Juan Manuel, Perez, Marco, Perry, James, Peters, Ulrike, Peyser, Patricia, Phillips, Lawrence S., Pleiness, Jacob, Pollin, Toni, Post, Wendy, Powers Becker, Julia, Preethi Boorgula, Meher, Preuss, Michael, Psaty, Bruce, Qasba, Pankaj, Qiao, Dandi, Qin, Zhaohui, Rafaels, Nicholas, Raffield, Laura, Rajendran, Mahitha, Ramachandran, Vasan S., Rao, D.C., Rasmussen-Torvik, Laura, Ratan, Aakrosh, Redline, Susan, Reed, Robert, Reeves, Catherine, Regan, Elizabeth, Reiner, Alex, Reupena, Muagututi‘a Sefuiva, Rice, Ken, Rich, Stephen, Robillard, Rebecca, Robine, Nicolas, Roden, Dan, Roselli, Carolina, Rotter, Jerome, Ruczinski, Ingo, Runnels, Alexi, Russell, Pamela, Ruuska, Sarah, Ryan, Kathleen, Sabino, Ester Cerdeira, Saleheen, Danish, Salimi, Shabnam, Salvi, Sejal, Salzberg, Steven, Sandow, Kevin, Sankaran, Vijay G., Santibanez, Jireh, Schwander, Karen, Schwartz, David, Sciurba, Frank, Seidman, Christine, Seidman, Jonathan, Sériès, Frédéric, Sheehan, Vivien, Sherman, Stephanie L., Shetty, Amol, Shetty, Aniket, Sheu, Wayne Hui-Heng, Shoemaker, M. Benjamin, Silver, Brian, Silverman, Edwin, Skomro, Robert, Smith, Albert Vernon, Smith, Jennifer, Smith, Josh, Smith, Nicholas, Smith, Tanja, Smoller, Sylvia, Snively, Beverly, Snyder, Michael, Sofer, Tamar, Sotoodehnia, Nona, Stilp, Adrienne M., Storm, Garrett, Streeten, Elizabeth, Su, Jessica Lasky, Sung, Yun Ju, Sylvia, Jody, Szpiro, Adam, Taliun, Daniel, Tang, Hua, Taub, Margaret, Taylor, Kent, Taylor, Matthew, Taylor, Simeon, Telen, Marilyn, Thornton, Timothy A., Threlkeld, Machiko, Tinker, Lesley, Tirschwell, David, Tishkoff, Sarah, Tiwari, Hemant, Tong, Catherine, Tracy, Russell, Tsai, Michael, Vaidya, Dhananjay, Van Den Berg, David, VandeHaar, Peter, Vrieze, Scott, Walker, Tarik, Wallace, Robert, Walts, Avram, Wang, Fei Fei, Wang, Heming, Wang, Jiongming, Watson, Karol, Watt, Jennifer, Weeks, Daniel E., Weinstock, Joshua, Weir, Bruce, Weiss, Scott T., Weng, Lu-Chen, Wessel, Jennifer, Willer, Cristen, Williams, Kayleen, Williams, L. Keoki, Williams, Scott, Wilson, Carla, Wilson, James, Winterkorn, Lara, Wong, Quenna, Wu, Baojun, Wu, Joseph, Xu, Huichun, Yanek, Lisa, Yang, Ivana, Yu, Ketian, Zekavat, Seyedeh Maryam, Zhang, Yingze, Zhao, Snow Xueyan, Zhao, Wei, Zhu, Xiaofeng, Ziv, Elad, Zody, Michael, Zoellner, Sebastian, Recto, Kathryn, Kachroo, Priyadarshini, Huan, Tianxiao, Lee, Gha Young, Bui, Helena, Lee, Dong Heon, Gereige, Jessica, Yao, Chen, Hwang, Shih-Jen, Joehanes, Roby, O’Connor, George T., and DeMeo, Dawn L.

Published
2023
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22. Genetic diversity fuels gene discovery for tobacco and alcohol use

Author

Saunders, Gretchen R. B., Wang, Xingyan, Chen, Fang, Jang, Seon-Kyeong, Liu, Mengzhen, Wang, Chen, Gao, Shuang, Jiang, Yu, Khunsriraksakul, Chachrit, Otto, Jacqueline M., Addison, Clifton, Akiyama, Masato, Albert, Christine M., Aliev, Fazil, Alonso, Alvaro, Arnett, Donna K., Ashley-Koch, Allison E., Ashrani, Aneel A., Barnes, Kathleen C., Barr, R. Graham, Bartz, Traci M., Becker, Diane M., Bielak, Lawrence F., Benjamin, Emelia J., Bis, Joshua C., Bjornsdottir, Gyda, Blangero, John, Bleecker, Eugene R., Boardman, Jason D., Boerwinkle, Eric, Boomsma, Dorret I., Boorgula, Meher Preethi, Bowden, Donald W., Brody, Jennifer A., Cade, Brian E., Chasman, Daniel I., Chavan, Sameer, Chen, Yii-Der Ida, Chen, Zhengming, Cheng, Iona, Cho, Michael H., Choquet, Hélène, Cole, John W., Cornelis, Marilyn C., Cucca, Francesco, Curran, Joanne E., de Andrade, Mariza, Dick, Danielle M., Docherty, Anna R., Duggirala, Ravindranath, Eaton, Charles B., Ehringer, Marissa A., Esko, Tõnu, Faul, Jessica D., Silva, Lilian Fernandes, Fiorillo, Edoardo, Fornage, Myriam, Freedman, Barry I., Gabrielsen, Maiken E., Garrett, Melanie E., Gharib, Sina A., Gieger, Christian, Gillespie, Nathan, Glahn, David C., Gordon, Scott D., Gu, Charles C., Gu, Dongfeng, Gudbjartsson, Daniel F., Guo, Xiuqing, Haessler, Jeffrey, Hall, Michael E., Haller, Toomas, Harris, Kathleen Mullan, He, Jiang, Herd, Pamela, Hewitt, John K., Hickie, Ian, Hidalgo, Bertha, Hokanson, John E., Hopfer, Christian, Hottenga, JoukeJan, Hou, Lifang, Huang, Hongyan, Hung, Yi-Jen, Hunter, David J., Hveem, Kristian, Hwang, Shih-Jen, Hwu, Chii-Min, Iacono, William, Irvin, Marguerite R., Jee, Yon Ho, Johnson, Eric O., Joo, Yoonjung Y., Jorgenson, Eric, Justice, Anne E., Kamatani, Yoichiro, Kaplan, Robert C., Kaprio, Jaakko, Kardia, Sharon L. R., Keller, Matthew C., Kelly, Tanika N., Kooperberg, Charles, Korhonen, Tellervo, Kraft, Peter, Krauter, Kenneth, Kuusisto, Johanna, Laakso, Markku, Lasky-Su, Jessica, Lee, Wen-Jane, Lee, James J., Levy, Daniel, Li, Liming, Li, Kevin, Li, Yuqing, Lin, Kuang, Lind, Penelope A., Liu, Chunyu, Lloyd-Jones, Donald M., Lutz, Sharon M., Ma, Jiantao, Mägi, Reedik, Manichaikul, Ani, Martin, Nicholas G., Mathur, Ravi, Matoba, Nana, McArdle, Patrick F., McGue, Matt, McQueen, Matthew B., Medland, Sarah E., Metspalu, Andres, Meyers, Deborah A., Millwood, Iona Y., Mitchell, Braxton D., Mohlke, Karen L., Moll, Matthew, Montasser, May E., Morrison, Alanna C., Mulas, Antonella, Nielsen, Jonas B., North, Kari E., Oelsner, Elizabeth C., Okada, Yukinori, Orrù, Valeria, Palmer, Nicholette D., Palviainen, Teemu, Pandit, Anita, Park, S. Lani, Peters, Ulrike, Peters, Annette, Peyser, Patricia A., Polderman, Tinca J. C., Rafaels, Nicholas, Redline, Susan, Reed, Robert M., Reiner, Alex P., Rice, John P., Rich, Stephen S., Richmond, Nicole E., Roan, Carol, Rotter, Jerome I., Rueschman, Michael N., Runarsdottir, Valgerdur, Saccone, Nancy L., Schwartz, David A., Shadyab, Aladdin H., Shi, Jingchunzi, Shringarpure, Suyash S., Sicinski, Kamil, Skogholt, Anne Heidi, Smith, Jennifer A., Smith, Nicholas L., Sotoodehnia, Nona, Stallings, Michael C., Stefansson, Hreinn, Stefansson, Kari, Stitzel, Jerry A., Sun, Xiao, Syed, Moin, Tal-Singer, Ruth, Taylor, Amy E., Taylor, Kent D., Telen, Marilyn J., Thai, Khanh K., Tiwari, Hemant, Turman, Constance, Tyrfingsson, Thorarinn, Wall, Tamara L., Walters, Robin G., Weir, David R., Weiss, Scott T., White, Wendy B., Whitfield, John B., Wiggins, Kerri L., Willemsen, Gonneke, Willer, Cristen J., Winsvold, Bendik S., Xu, Huichun, Yanek, Lisa R., Yin, Jie, Young, Kristin L., Young, Kendra A., Yu, Bing, Zhao, Wei, Zhou, Wei, Zöllner, Sebastian, Zuccolo, Luisa, Batini, Chiara, Bergen, Andrew W., Bierut, Laura J., David, Sean P., Gagliano Taliun, Sarah A., Hancock, Dana B., Jiang, Bibo, Munafò, Marcus R., Thorgeirsson, Thorgeir E., Liu, Dajiang J., and Vrieze, Scott

Published
2022
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24. Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants.

Author

Zhao, Xutong, Qiao, Dandi, Yang, Chaojie, Kasela, Silva, Kim, Wonji, Ma, Yanlin, Shrine, Nick, Batini, Chiara, Sofer, Tamar, Taliun, Sarah A Gagliano, Sakornsakolpat, Phuwanat, Balte, Pallavi P, Prokopenko, Dmitry, Yu, Bing, Lange, Leslie A, Dupuis, Josée, Cade, Brian E, Lee, Jiwon, Gharib, Sina A, Daya, Michelle, Laurie, Cecelia A, Ruczinski, Ingo, Cupples, L Adrienne, Loehr, Laura R, Bartz, Traci M, Morrison, Alanna C, Psaty, Bruce M, Vasan, Ramachandran S, Wilson, James G, Taylor, Kent D, Durda, Peter, Johnson, W Craig, Cornell, Elaine, Guo, Xiuqing, Liu, Yongmei, Tracy, Russell P, Ardlie, Kristin G, Aguet, François, VanDenBerg, David J, Papanicolaou, George J, Rotter, Jerome I, Barnes, Kathleen C, Jain, Deepti, Nickerson, Deborah A, Muzny, Donna M, Metcalf, Ginger A, Doddapaneni, Harshavardhan, Dugan-Perez, Shannon, Gupta, Namrata, Gabriel, Stacey, Rich, Stephen S, O'Connor, George T, Redline, Susan, Reed, Robert M, Laurie, Cathy C, Daviglus, Martha L, Preudhomme, Liana K, Burkart, Kristin M, Kaplan, Robert C, Wain, Louise V, Tobin, Martin D, London, Stephanie J, Lappalainen, Tuuli, Oelsner, Elizabeth C, Abecasis, Goncalo R, Silverman, Edwin K, Barr, R Graham, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Cho, Michael H, and Manichaikul, Ani

Subjects
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed Lung Working Group, Lung, Humans, Pulmonary Disease, Chronic Obstructive, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Small Ubiquitin-Related Modifier Proteins, Follow-Up Studies, Feasibility Studies, Polymorphism, Single Nucleotide, Adult, Aged, Aged, 80 and over, Middle Aged, African Americans, Female, Male, Protein Inhibitors of Activated STAT, Respiratory Physiological Phenomena, Genome-Wide Association Study, Genetic Loci, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Whole Genome Sequencing, and over, Polymorphism, Single Nucleotide, Pulmonary Disease, Chronic Obstructive
Abstract

Chronic obstructive pulmonary disease (COPD), diagnosed by reduced lung function, is a leading cause of morbidity and mortality. We performed whole genome sequence (WGS) analysis of lung function and COPD in a multi-ethnic sample of 11,497 participants from population- and family-based studies, and 8499 individuals from COPD-enriched studies in the NHLBI Trans-Omics for Precision Medicine (TOPMed) Program. We identify at genome-wide significance 10 known GWAS loci and 22 distinct, previously unreported loci, including two common variant signals from stratified analysis of African Americans. Four novel common variants within the regions of PIAS1, RGN (two variants) and FTO show evidence of replication in the UK Biobank (European ancestry n ~ 320,000), while colocalization analyses leveraging multi-omic data from GTEx and TOPMed identify potential molecular mechanisms underlying four of the 22 novel loci. Our study demonstrates the value of performing WGS analyses and multi-omic follow-up in cohorts of diverse ancestry.

Published
2020

25. Evaluating Airsoft Electric Guns for Control of Invasive Brown Treesnakes

Author

Knox, Adam J., Lardner, Björn, Adams, Amy Yackel, and Reed, Robert N.

Subjects
Boiga irregularis, brown treesnake, Guam, invasive species, pest control, rapid response, regulations, safety, specimen collection
Abstract

Firearms are often used in lethal control of invasive vertebrates, but safety and regulatory aspects limit the circumstances under which they can be used. During August 2016 at the Brown Treesnake Project laboratory on Guam, we evaluated hobby‐grade Airsoft Electric Guns (AEGs; a lower powered, less‐hazardous, and less‐regulated alternative to firearms) for capture and control of small animals, with specific emphasis on invasive brown treesnakes (Boiga irregularis). Tests of AEGs differing in power with ammunition (plastic pellets) masses ranging from 0.20 to 0.39 g, fired at gelatin blocks from distances of 4, 8, and 12 m, showed that heavy ammunition is of overriding importance for maximizing lethality: 0.39‐g pellets penetrated more deeply at 12 m than did 0.20‐g pellets at 4 m. Inspection of tissue damage in brown treesnake carcasses subjected to fire with the 0.39‐g ammunition from the same distances suggested that injuries sustained by a direct hit from 12 m would often be lethal, and snakes would be unlikely to survive multiple hits from automatic fire discharged at approximately 17/s. Limited trials with live snakes helped us to understand behavioral responses in a snake hit by ≥1 pellets, including distance traveled over time. Based on these factors, we assessed the risk that a snake injured by pellet fire might evade subsequent capture by rapid responders in the proximity. We also discuss ethical considerations and regulatory advantages of using AEGs.

Published
2020

26. Metoprolol for the Prevention of Acute Exacerbations of COPD

Author

Dransfield, Mark T, Voelker, Helen, Bhatt, Surya P, Brenner, Keith, Casaburi, Richard, Come, Carolyn E, Cooper, J Allen D, Criner, Gerard J, Curtis, Jeffrey L, Han, MeiLan K, Hatipoğlu, Umur, Helgeson, Erika S, Jain, Vipul V, Kalhan, Ravi, Kaminsky, David, Kaner, Robert, Kunisaki, Ken M, Lambert, Allison A, Lammi, Matthew R, Lindberg, Sarah, Make, Barry J, Martinez, Fernando J, McEvoy, Charlene, Panos, Ralph J, Reed, Robert M, Scanlon, Paul D, Sciurba, Frank C, Smith, Anthony, Sriram, Peruvemba S, Stringer, William W, Weingarten, Jeremy A, Wells, J Michael, Westfall, Elizabeth, Lazarus, Stephen C, and Connett, John E

Subjects
Clinical Trials and Supportive Activities, Chronic Obstructive Pulmonary Disease, Lung, Clinical Research, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Respiratory, Adrenergic beta-1 Receptor Antagonists, Aged, Aged, 80 and over, Disease Progression, Female, Forced Expiratory Volume, Hospitalization, Humans, Kaplan-Meier Estimate, Male, Metoprolol, Middle Aged, Prospective Studies, Pulmonary Disease, Chronic Obstructive, Treatment Failure, BLOCK COPD Trial Group, Medical and Health Sciences, General & Internal Medicine
Abstract

BackgroundObservational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.MethodsIn this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.ResultsA total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.ConclusionsAmong patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).

Published
2019

27. Best, Last, Only

Author

Reed, Robert, American writer

Subjects
Best, Last, Only (Novella), Literature/writing
Abstract

BEST 1 THE HUMAN WALKED INTO the couloir, lowering his bones and folding his meat before pressing that gruesome and very tiny face against the ceremonial ground. One enthusiastic bite [...]

Published
2023

29. Novel Antimycobacterial Compounds Suppress NAD Biogenesis by Targeting a Unique Pocket of NaMN Adenylyltransferase

Author

Osterman, Andrei L, Rodionova, Irina, Li, Xiaoqing, Sergienko, Eduard, Ma, Chen-Ting, Catanzaro, Antonino, Pettigrove, Mark E, Reed, Robert W, Gupta, Rashmi, Rohde, Kyle H, Korotkov, Konstantin V, and Sorci, Leonardo

Subjects
Biological Sciences, Medicinal and Biomolecular Chemistry, Chemical Sciences, Tuberculosis, Orphan Drug, Biodefense, Prevention, Infectious Diseases, Vaccine Related, Antimicrobial Resistance, Rare Diseases, Emerging Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Antitubercular Agents, Drug Resistance, Bacterial, Microbial Sensitivity Tests, Mycobacterium tuberculosis, NAD, Nicotinamide-Nucleotide Adenylyltransferase, Structure-Activity Relationship, Organic Chemistry, Biological sciences, Chemical sciences
Abstract

Conventional treatments to combat the tuberculosis (TB) epidemic are falling short, thus encouraging the search for novel antitubercular drugs acting on unexplored molecular targets. Several whole-cell phenotypic screenings have delivered bioactive compounds with potent antitubercular activity. However, their cellular target and mechanism of action remain largely unknown. Further evaluation of these compounds may include their screening in search for known antitubercular drug targets hits. Here, a collection of nearly 1400 mycobactericidal compounds was screened against Mycobacterium tuberculosis NaMN adenylyltransferase ( MtNadD), a key enzyme in the biogenesis of NAD cofactor that was recently validated as a new drug target for dormant and active tuberculosis. We found three chemotypes that efficiently inhibit MtNadD in the low micromolar range in vitro. SAR and cheminformatics studies of commercially available analogues point to a series of benzimidazolium derivatives, here named N2, with bactericidal activity on different mycobacteria, including M. abscessus, multidrug-resistant M. tuberculosis, and dormant M. smegmatis. The on-target activity was supported by the increased resistance of an M. smegmatis strain overexpressing the target and by a rapid decline in NAD(H) levels. A cocrystal structure of MtNadD with N2-8 inhibitor reveals that the binding of the inhibitor induced the formation of a new quaternary structure, a dimer-of-dimers where two copies of the inhibitor occupy symmetrical positions in the dimer interface, thus paving the way for the development of a new generation of selective MtNadD bioactive inhibitors. All these results strongly suggest that pharmacological inhibition of MtNadD is an effective strategy to combat dormant and resistant Mtb strains.

Published
2019

30. Structural Variability of EspG Chaperones from Mycobacterial ESX-1, ESX-3, and ESX-5 Type VII Secretion Systems

Author

Tuukkanen, Anne T, Freire, Diana, Chan, Sum, Arbing, Mark A, Reed, Robert W, Evans, Timothy J, Zenkeviciutė, Grasilda, Kim, Jennifer, Kahng, Sara, Sawaya, Michael R, Chaton, Catherine T, Wilmanns, Matthias, Eisenberg, David, Parret, Annabel HA, and Korotkov, Konstantin V

Subjects
Biochemistry and Cell Biology, Biological Sciences, Underpinning research, 1.1 Normal biological development and functioning, Good Health and Well Being, Amino Acid Sequence, Antigens, Bacterial, Bacterial Proteins, Binding Sites, Molecular Chaperones, Mycobacterium tuberculosis, Protein Conformation, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Type VII Secretion Systems, Virulence Factors, protein export, small-angle X-ray scattering, PE-PPE proteins, PE–PPE proteins, Medicinal and Biomolecular Chemistry, Microbiology, Biochemistry & Molecular Biology, Biochemistry and cell biology
Abstract

Type VII secretion systems (ESX) are responsible for transport of multiple proteins in mycobacteria. How different ESX systems achieve specific secretion of cognate substrates remains elusive. In the ESX systems, the cytoplasmic chaperone EspG forms complexes with heterodimeric PE-PPE substrates that are secreted from the cells or remain associated with the cell surface. Here we report the crystal structure of the EspG1 chaperone from the ESX-1 system determined using a fusion strategy with T4 lysozyme. EspG1 adopts a quasi 2-fold symmetric structure that consists of a central β-sheet and two α-helical bundles. In addition, we describe the structures of EspG3 chaperones from four different crystal forms. Alternate conformations of the putative PE-PPE binding site are revealed by comparison of the available EspG3 structures. Analysis of EspG1, EspG3, and EspG5 chaperones using small-angle X-ray scattering reveals that EspG1 and EspG3 chaperones form dimers in solution, which we observed in several of our crystal forms. Finally, we propose a model of the ESX-3 specific EspG3-PE5-PPE4 complex based on the small-angle X-ray scattering analysis.

Published
2019

31. Serum IgG subclass levels and risk of exacerbations and hospitalizations in patients with COPD

Author

Leitao Filho, Fernando Sergio, Ra, Seung Won, Mattman, Andre, Schellenberg, Robert S, Criner, Gerard J, Woodruff, Prescott G, Lazarus, Stephen C, Albert, Richard, Connett, John E, Han, Meilan K, Martinez, Fernando J, Leung, Janice M, Paul Man, SF, Aaron, Shawn D, Reed, Robert M, Sin, Don D, and for the Canadian Respiratory Research Network (CRRN)

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Prevention, Clinical Research, Lung, Chronic Obstructive Pulmonary Disease, Respiratory, Aged, Biomarkers, Double-Blind Method, Female, Hospitalization, Humans, IgG Deficiency, Immunoglobulin G, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Retrospective Studies, Risk Factors, IgG, IgG subclass deficiency, COPD, Exacerbation, Canadian Respiratory Research Network, Cardiorespiratory Medicine and Haematology, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundThe literature is scarce regarding the prevalence and clinical impact of IgG subclass deficiency in COPD. We investigated the prevalence of IgG subclass deficiencies and their association with exacerbations and hospitalizations using subjects from two COPD cohorts.MethodsWe measured IgG subclass levels using immunonephelometry in serum samples from participants enrolled in two previous COPD trials: Macrolide Azithromycin for Prevention of Exacerbations of COPD (MACRO; n = 976) and Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE; n = 653). All samples were collected from clinically stable participants upon entry into both studies. IgG subclass deficiency was diagnosed when IgG subclass levels were below their respective lower limit of normal: IgG1

Published
2018

34. The ivory lncRNA regulates seasonal color patterns in buckeye butterflies.

Author

Fandino, Richard A., Brady, Noah K., Chatterjee, Martik, McDonald, Jeanne M. C., Livraghi, Luca, van der Burg, Karin R. L., Mazo-Vargas, Anyi, Markenscoff-Papadimitriou, Eirene, and Reed, Robert D.

Subjects
LINCRNA, NON-coding RNA, GENE expression, IVORY, PHENOTYPES
Abstract

Long noncoding RNAs (lncRNAs) are transcribed elements increasingly recognized for their roles in regulating gene expression. Thus far, however, we have little understanding of how lncRNAs contribute to evolution and adaptation. Here, we show that a conserved lncRNA, ivory, is an important color patterning gene in the buckeye butterfly Junonia coenia. ivory overlaps with cortex, a locus linked to multiple cases of crypsis and mimicry in Lepidoptera. Along with a companion paper by Livraghi et al., we argue that ivory, not cortex, is the color pattern gene of interest at this locus. In J. coenia, a cluster of cis-regulatory elements (CREs) in the first intron of ivory are genetically associated with natural variation in seasonal color pattern plasticity, and targeted deletions of these CREs phenocopy seasonal phenotypes. Deletions of different ivory CREs produce other distinct phenotypes as well, including loss of melanic eyespot rings, and positive and negative changes in overall wing pigmentation. We show that the color pattern transcription factors Spineless, Bric-a-brac, and Ftz-f1 bind to the ivory promoter during wing pattern development, suggesting that they directly regulate ivory. This case study demonstrates how cis-regulation of a single noncoding RNA can exert diverse and nuanced effects on the evolution and development of color patterns, including modulating seasonally plastic color patterns. [ABSTRACT FROM AUTHOR]

Published
2024
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35. The Size Distribution of the Banking Sector and Financial Fragility.

Author

GAO, JIAHONG and REED, ROBERT R.

Subjects
BANKING industry, FINANCIAL bailouts, INTERMEDIATION (Finance), SUNSPOTS (Economics)
Abstract

We study the role of the size distribution of the banking sector for bailout policy and financial fragility in a model of financial intermediation with limited commitment and noisy sunspots. In particular, due to the different costs of mitigating depositors' losses, differences in financial fragility arise endogenously in the sense that the large banking market admits a higher degree of instability. Moreover, the desire to reduce differences in the amount of bailout funding across segments of the banking system leads the fiscal authority to collect less taxes ex‐ante but ends up rendering the scope for run equilibria larger. [ABSTRACT FROM AUTHOR]

Published
2024
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36. A long noncoding RNA at the cortex locus controls adaptive coloration in butterflies.

Author

Livraghi, Luca, Hanly, Joseph J., Evans, Elizabeth, Wright, Charlotte J., Ling S. Loh, Mazo-Vargas, Anyi, Kamrava, Kiana, Carter, Alexander, van der Heijden, Eva S. M., Reed, Robert D., Papa, Riccardo, Jiggins, Chris D., and Martin, Arnaud

Subjects
LINCRNA, LOCUS of control, ADAPTIVE control systems, PHENOTYPES, BUTTERFLIES
Abstract

Evolutionary variation in the wing pigmentation of butterflies and moths offers striking examples of adaptation by crypsis and mimicry. The cortex locus has been independently mapped as the locus controlling color polymorphisms in 15 lepidopteran species, suggesting that it acts as a genomic hotspot for the diversification of wing patterns, but functional validation through protein-coding knockouts has proven difficult to obtain. Our study unveils the role of a long noncoding RNA (lncRNA) which we name ivory, transcribed from the cortex locus, in modulating color patterning in butterflies. Strikingly, ivory expression prefigures most melanic patterns during pupal development, suggesting an early developmental role in specifying scale identity. To test this, we generated CRISPR mosaic knock-outs in five nymphalid butterfly species and show that ivory mutagenesis yields transformations of dark pigmented scales into white or light-colored scales. Genotyping of Vanessa cardui germline mutants associates these phenotypes to small on-target deletions at the conserved first exon of ivory. In contrast, cortex germline mutant butterflies with confirmed null alleles lack any wing phenotype and exclude a color patterning role for this adjacent gene. Overall, these results show that a lncRNA gene acts as a master switch of color pattern specification and played key roles in the adaptive diversification of wing patterns in butterflies. [ABSTRACT FROM AUTHOR]

Published
2024
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37. Azithromycin and risk of COPD exacerbations in patients with and without Helicobacter pylori

Author

Ra, Seung Won, Sze, Marc A, Lee, Eun Chong, Tam, Sheena, Oh, Yeni, Fishbane, Nick, Criner, Gerard J, Woodruff, Prescott G, Lazarus, Stephen C, Albert, Richard, Connett, John E, Han, Meilan K, Martinez, Fernando J, Aaron, Shawn D, Reed, Robert M, Man, SF Paul, Sin, Don D, and on behalf of the Canadian Respiratory Research Network

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Lung, Chronic Obstructive Pulmonary Disease, Respiratory, Aged, Anti-Bacterial Agents, Antibodies, Bacterial, Azithromycin, Biomarkers, C-Reactive Protein, Disease Progression, Disease-Free Survival, Female, Helicobacter Infections, Helicobacter pylori, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Pulmonary Disease, Chronic Obstructive, Receptors, Tumor Necrosis Factor, Type II, Risk Factors, Serologic Tests, Time Factors, Treatment Outcome, COPD, Exacerbation, Canadian Respiratory Research Network, Cardiorespiratory Medicine and Haematology, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundHelicobacter pylori (HP) infection is associated with reduced lung function and systemic inflammation in chronic obstructive pulmonary disease (COPD) patients. Azithromycin (AZ) is active against HP and reduces the risk of COPD exacerbation. We determined whether HP infection status modifies the effects of AZ in COPD patients.MethodsPlasma samples from 1018 subjects with COPD who participated in the Macrolide Azithromycin (MACRO) in COPD Study were used to determine the HP infection status at baseline and 12 months of follow-up using a serologic assay. Based on HP infection status and randomization to either AZ or placebo (PL), the subjects were divided into 4 groups: HP+/AZ, HP-/AZ, HP+/PL, and HP-/PL. Time to first exacerbation was compared across the 4 groups using Kaplan-Meier survival analysis and a Cox proportional hazards model. The rates of exacerbation were compared using both the Kruskal-Wallis test and negative binomial analysis. Blood biomarkers at enrolment and at follow-up visits 3, 12, and 13 (1 month after treatment was stopped) months were measured.ResultsOne hundred eighty one (17.8%) patients were seropositive to HP. Non-Caucasian participants were nearly three times more likely to be HP seropositive than Caucasian participants (37.4% vs 13.6%; p

Published
2017

38. Effect of beta-blockers on exacerbation rate and lung function in chronic obstructive pulmonary disease (COPD)

Author

Duffy, Sean, Marron, Robert, Voelker, Helen, Albert, Richard, Connett, John, Bailey, William, Casaburi, Richard, Cooper, J Allen, Curtis, Jeffrey L, Dransfield, Mark, Han, MeiLan K, Make, Barry, Marchetti, Nathaniel, Martinez, Fernando, Lazarus, Stephen, Niewoehner, Dennis, Scanlon, Paul D, Sciurba, Frank, Scharf, Steven, Reed, Robert M, Washko, George, Woodruff, Prescott, McEvoy, Charlene, Aaron, Shawn, Sin, Don, Criner, Gerard J, and the NIH COPD Clinical Research Network and the Canadian Institutes of Health Research

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Chronic Obstructive Pulmonary Disease, Clinical Trials and Supportive Activities, Clinical Research, Heart Disease, Lung, Cardiovascular, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Respiratory, Adrenergic beta-Antagonists, Aged, Cohort Studies, Female, Follow-Up Studies, Humans, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests, Retrospective Studies, Treatment Outcome, COPD, Exacerbation, Beta-blocker, NIH COPD Clinical Research Network and the Canadian Institutes of Health Research, Cardiorespiratory Medicine and Haematology, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract

BackgroundBeta-blockers are commonly prescribed for patients with cardiovascular disease. Providers have been wary of treating chronic obstructive pulmonary disease (COPD) patients with beta-blockers due to concern for bronchospasm, but retrospective studies have shown that cardio-selective beta-blockers are safe in COPD and possibly beneficial. However, these benefits may reflect symptom improvements due to the cardiac effects of the medication. The purpose of this study is to evaluate associations between beta-blocker use and both exacerbation rates and longitudinal measures of lung function in two well-characterized COPD cohorts.MethodsWe retrospectively analyzed 1219 participants with over 180 days of follow up from the STATCOPE trial, which excluded most cardiac comorbidities, and from the placebo arm of the MACRO trial. Primary endpoints were exacerbation rates per person-year and change in spirometry over time in association with beta blocker use.ResultsOverall 13.9% (170/1219) of participants reported taking beta-blockers at enrollment. We found no statistically significant differences in exacerbation rates with respect to beta-blocker use regardless of the prevalence of cardiac comorbidities. In the MACRO cohort, patients taking beta-blockers had an exacerbation rate of 1.72/person-year versus a rate of 1.71/person-year in patients not taking beta-blockers. In the STATCOPE cohort, patients taking beta-blockers had an exacerbation rate of 1.14/person-year. Patients without beta-blockers had an exacerbation rate of 1.34/person-year. We found no detrimental effect of beta blockers with respect to change in lung function over time.ConclusionWe found no evidence that beta-blocker use was unsafe or associated with worse pulmonary outcomes in study participants with moderate to severe COPD.

Published
2017

39. β-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction

Author

LaFon, David C., primary, Helgeson, Erika S., additional, Lindberg, Sarah, additional, Voelker, Helen, additional, Bhatt, Surya P., additional, Casaburi, Richard, additional, Cassady, Steven J., additional, Connett, John, additional, Criner, Gerard J., additional, Hatipoglu, Umur, additional, Kaminsky, David A., additional, Kunisaki, Ken M., additional, Lazarus, Stephen C., additional, McEvoy, Charlene E., additional, Reed, Robert M., additional, Sciurba, Frank C., additional, Stringer, William, additional, and Dransfield, Mark T., additional

Published
2024
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50. Phenomenology of additional scalar bosons at the LHC

Author

Kumar, Mukesh, von Buddenbrock, Stefan, Chakrabarty, Nabarun, Cornell, Alan S., Kar, Deepak, Mandal, Tanumoy, Mellado, Bruce, Mukhopadhyaya, Biswarup, Reed, Robert G., and Ruan, Xifeng

Subjects
High Energy Physics - Phenomenology
Abstract

The confirmation of the Higgs boson in Run I data at the Large Hadron Collider (LHC) and the excesses in recent Run II data suggest scenarios beyond the Standard Model (SM). We pursue a study in a minimal model which is an extension of a scalar doublet in the SM known as two-Higgs doublet model (THDM). Following earlier suggestions two real scalars $\chi$ and $S$ have been introduced in the THDM where $\chi$ is treated as a candidate for dark matter. $\chi$ does not receive any vacuum expectation value ($vev$) in the model whereas the Higgs-like scalar $S$ acquires $vev$. This allows small mixing between the $CP$-even scalars of the THDM, $h$, $H$ and $S$. In this study the mass spectrum of new scalars is taken to be $2 m_h < m_H < 2 m_t$, $m_\chi < m_h/2$, $m_h \lesssim m_S \lesssim m_H - m_h$, $m_A > 2 m_t$ and $m_H^\pm < m_A$, where $m_h$ and $m_t$ is masses of the SM Higgs and top-quark respectively, $m_H, m_A$ and $m_{H^\pm}$ are the masses of the heavy $CP$-even scalar $H$, $CP$-odd scalar $A$, and charged Higgs $H^\pm$, respectively. A partial list of potential search channels at the LHC has been provided with possible phenomenological consequences. The expected phenomenology and constraints on parameters are also discussed in a model-independent approach ., Comment: 5 pages, 2 tables, submitted to SAIP 2016, South Africa proceedings

Published
2016

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