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1. Comparison of Superior versus Inferior Canaloplasty and Trabeculotomy Using the OMNI Surgical System

Author

Noh SH, Smith AK, Fox AR, Gustafson KM, Kwan CC, Lin KY, and Mosaed S

Subjects
omni, canaloplasty, trabeculotomy, goniotomy, migs, Ophthalmology, RE1-994
Abstract

Stephanie H Noh,1– 3 Andrew K Smith,1– 3 Austin R Fox,1– 3 Kevin M Gustafson,1– 3 Changyow C Kwan,1– 3 Ken Y Lin,1,2,4 Sameh Mosaed1,2 1University of California, Irvine School of Medicine, Irvine, CA, 92617, USA; 2Gavin Herbert Eye Institute, Department of Ophthalmology, UC Irvine, Irvine, CA, 92617, USA; 3Tibor Rubin Veteran Affairs Medical Center, Long Beach, CA, 90822, USA; 4Department of Biomedical Engineering, UC Irvine, Irvine, CA, 92617, USACorrespondence: Stephanie H Noh, Gavin Herbert Eye Institute, University of California, Irvine, USA, 850 Health Sciences Road, Irvine, CA, 92617, USA, Tel +1-951-751-7971, Fax +1-949-824-2073, Email shnoh1@hs.uci.eduPurpose: To compare outcomes of ab-interno canaloplasty and trabeculotomy of the superior versus inferior angle.Patients and methods: This was a prospective, non-randomized, interventional comparison study done at the Veteran Affairs Hospital in Long Beach, California. All patients underwent cataract surgery with intraocular lens implantation combined with ab-interno canaloplasty and trabeculotomy with the OMNI Surgical System (SightSciences, Menlo Park, CA, USA), either superiorly or inferiorly. Pre- and post-operative intraocular pressure using Goldmann applanation tonometry and best corrected visual acuity were obtained and compared using paired t-tests. Patients were excluded if they had any prior intraocular surgery or prior laser trabeculoplasty procedures.Results: 38 eyes from 29 patients were analyzed. 19 eyes were included in the superior group and 19 eyes in the inferior group. Mean pre-operative IOP in the superior group was 17.6 ± 5.2 mmHg and in the inferior group was 17.6 ± 4.6 mmHg (p > 0.99). At 12 months, mean postoperative IOP for the superior group decreased 24% to 13.3 ± 2.8 mmHg while the inferior group decreased 26% to 13.1 ± 2.2 mmHg (p = 0.92). Mean preoperative medications in the superior group were 2.2 ± 1.3 and in the inferior group was 2.4 ± 1.3 (p = 0.88). At 12 months, this decreased to 1.3 ± 1.5 post-operatively in the superior group and 2.2 ± 1.6 post-operatively in the inferior group (p = 0.64).Conclusion: There was no statistical difference in efficacy between superior versus inferior canaloplasty/trabeculotomy with OMNI. Therefore, surgeons can perform the procedure in the direction that is most comfortable for them without affecting outcomes.Keywords: OMNI, canaloplasty, trabeculotomy, goniotomy, MIGS

Published
2024

2. Prospective Study of Canaloplasty and Trabeculotomy Performed by Trainees

Author

Smith AK, Kwan CC, Fox A, Noh S, Gustafson K, Lin KY, and Mosaed S

Subjects
omni, canaloplasty, trabeculotomy, goniotomy, migs, Ophthalmology, RE1-994
Abstract

Andrew K Smith,1– 3 Changyow C Kwan,1– 3 Austin Fox,1– 3 Stephanie Noh,1– 3 Kevin Gustafson,1– 3 Ken Y Lin,1,2,4 Sameh Mosaed1,2 1School of Medicine, University of California, Irvine, CA, USA; 2Department of Ophthalmology, Gavin Herbert Eye Institute, Irvine, CA, USA; 3Department of Ophthalmology, Tibor Rubin Veteran Affairs Medical Center, Long Beach, CA, USA; 4Department of Biomedical Engineering, University of California, Irvine, CA, USACorrespondence: Andrew K Smith, Gavin Herbert Eye Institute, University of California, 850 Health Sciences Road, Irvine, CA, 92697-4375, USA, Tel +1-949-824-7944, Fax +1-949-824-2073, Email andrewks@hs.uci.eduPurpose: To evaluate outcomes of new adopters of the OMNI® Surgical System (Sight Sciences, Inc.) by prospectively evaluating intermediate-term outcomes of patients operated by trainees.Patients and Methods: This was a prospective study of surgeries performed by trainees on patients with open angle glaucoma undergoing simultaneous cataract surgery and ab interno canaloplasty and trabeculotomy using the OMNI Surgical System. Pre-operative intraocular pressure (IOP) and number of glaucoma medications were recorded. Only patients with a minimum of 6-month follow up were included. Baseline IOP was used to separate subjects into two groups: Group 1 (IOP ≥ 18 mmHg) and Group 2 (IOP < 18 mmHg). Mean decrease in IOP and medications was calculated and compared with paired t-tests for the overall sample as well as the subgroups. Success was defined as those with a ≥ 20% reduction from pre-operative IOP or with an IOP ≤ 18 mmHg and ≥ 6 mmHg and on the same or fewer number of medications while not requiring additional surgery. Adverse events were also recorded.Results: Forty-two eyes of 31 patients were included. Mean pre-operative IOP was 17.2 ± 4.8 mmHg and mean number of medications was 2.4 ± 1.2. The primary endpoint was reached in 83.3% of patients at 12 months. IOP was reduced by 22.3% to 13.4 ± 2.4 (p< 0.001). Mean number of medications decreased to 1.7 ± 1.6 (p< 0.001). Group 1 mean IOP decreased 35.4% from 22.2 ± 4.6 mmHg to 14.3 ± 2.8 mmHg (p< 0.001). Group 2 mean number of medications decreased from 2.3 ± 1.1 to 1.6 ± 1.5 (p< 0.001).Conclusion: When operated on by the novice MIGS surgeon, the OMNI device provides effective IOP and glaucoma medication reduction with minimal adverse events. Efficacy and safety of the device in the hands of trainees was comparable to experienced glaucoma surgeons suggesting its ease of adoption.Keywords: OMNI, canaloplasty, trabeculotomy, goniotomy, MIGs, minimally invasive glaucoma surgeries

Published
2024

3. Insights into genetic susceptibility in the etiology of spontaneous preterm birth

Author

Parets SE, Knight AK, and Smith AK

Subjects
PTB, GWAS, linkage, candidate gene, African American, epigenetic, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Sasha E Parets,1 Anna K Knight,2 Alicia K Smith,1,2 1Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA; 2Genetics and Molecular Biology Program, Emory University, Atlanta, GA, USA Abstract: Preterm birth (PTB;

Published
2015

5. Discrimination in Healthcare Settings is Associated with Disability in Older Adults: Health and Retirement Study, 2008–2012

Author

Rogers, SE, Thrasher, AD, Miao, Y, Boscardin, WJ, and Smith, AK

Subjects
General & Internal Medicine, Clinical Sciences
Abstract

BACKGROUND: As our society ages, improving medical care for an older population will be crucial. Discrimination in healthcare may contribute to substandard experiences with the healthcare system, increasing the burden of poor health in older adults. Few studies have focused on the presence of healthcare discrimination and its effects on older adults. OBJECTIVE: We aimed to examine the relationship between healthcare discrimination and new or worsened disability. DESIGN: This was a longitudinal analysis of data from the nationally representative Health and Retirement Study administered in 2008 with follow-up through 2012. PARTICIPANTS: Six thousand and seventeen adults over the age of 50 years (mean age 67 years, 56.3 % female, 83.1 % white) were included in this study. MAIN MEASURES: Healthcare discrimination assessed by a 2008 report of receiving poorer service or treatment than other people by doctors or hospitals (never, less than a year=infrequent; more than once a year=frequent). Outcome was self-report of new or worsened disability by 2012 (difficulty or dependence in any of six activities of daily living). We used a Cox proportional hazards model adjusting for age, race/ethnicity, gender, net worth, education, depression, high blood pressure, diabetes, cancer, lung disease, heart disease, stroke, and healthcare utilization in the past 2 years. KEY RESULTS: In all, 12.6 % experienced discrimination infrequently and 5.9 % frequently. Almost one-third of participants (29 %) reporting frequent healthcare discrimination developed new or worsened disability over 4 years, compared to 16.8 % of those who infrequently and 14.7 % of those who never experienced healthcare discrimination (p < 0.001). In multivariate analyses, compared to no discrimination, frequent healthcare discrimination was associated with new or worsened disability over 4 years (aHR = 1.63, 95 % CI 1.16–2.27). CONCLUSIONS: One out of five adults over the age of 50 years experiences discrimination in healthcare settings. One in 17 experience frequent healthcare discrimination, and this is associated with new or worsened disability by 4 years. Future research should focus on the mechanisms by which healthcare discrimination influences disability in older adults to promote better health outcomes for an aging population.

Published
2015

6. Discrimination in Healthcare Settings is Associated with Disability in Older Adults: Health and Retirement Study, 2008–2012

Author

Smith, Alexander, Rogers, SE, Thrasher, AD, Miao, Y, Boscardin, WJ, and Smith, AK

Abstract

© 2015 The Author(s) BACKGROUND: As our society ages, improving medical care for an older population will be crucial. Discrimination in healthcare may contribute to substandard experiences with the healthcare system, increasing the burden of poor health in

Published
2015

7. Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Author

Maihofer, AX, Choi, KW, Coleman, JR, Daskalakis, NP, Denckla, CA, Ketema, E, Morey, RA, Polimanti, R, Ratanatharathorn, A, Torres, K, Wingo, AP, Zai, CC, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Borglum, AD, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Chen, C-Y, Dale, AM, Dalvie, S, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Duncan, LE, Kulenovic, AD, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gautam, A, Gelaye, B, Gelernter, J, Geuze, E, Gillespie, CF, Goci, A, Gordon, SD, Guffanti, G, Hammamieh, R, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Logue, MW, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, JL, Marmar, C, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Michopoulos, V, Milberg, W, Miller, MW, Morris, CP, Mors, O, Mortensen, PB, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Yehuda, R, Young, KA, Young, RM, Zhao, H, Zoellner, LA, Haas, M, Lasseter, H, Provost, AC, Salem, RM, Sebat, J, Shaffer, RA, Wu, T, Ripke, S, Daly, MJ, Ressler, KJ, Koenen, KC, Stein, MB, Nievergelt, CM, Maihofer, AX, Choi, KW, Coleman, JR, Daskalakis, NP, Denckla, CA, Ketema, E, Morey, RA, Polimanti, R, Ratanatharathorn, A, Torres, K, Wingo, AP, Zai, CC, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Borglum, AD, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Chen, C-Y, Dale, AM, Dalvie, S, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Duncan, LE, Kulenovic, AD, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gautam, A, Gelaye, B, Gelernter, J, Geuze, E, Gillespie, CF, Goci, A, Gordon, SD, Guffanti, G, Hammamieh, R, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, C, Liberzon, I, Linnstaedt, SD, Logue, MW, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, JL, Marmar, C, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, Mehta, D, Mellor, R, Michopoulos, V, Milberg, W, Miller, MW, Morris, CP, Mors, O, Mortensen, PB, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, KJ, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Yehuda, R, Young, KA, Young, RM, Zhao, H, Zoellner, LA, Haas, M, Lasseter, H, Provost, AC, Salem, RM, Sebat, J, Shaffer, RA, Wu, T, Ripke, S, Daly, MJ, Ressler, KJ, Koenen, KC, Stein, MB, and Nievergelt, CM

Abstract

BACKGROUND: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs). METHODS: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms. RESULTS: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program. CONCLUSIONS: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods.

Published
2022

9. The Candida albicans Cdk8-dependent phosphoproteome reveals repression of hyphal growth through a Flo8-dependent pathway

Author

Zhongle Liu, Lawrence C. Myers, Jeffrey M. Hollomon, Smith Ak, Deborah A. Hogan, Nicole P. Jenkins, Scott F. Rusin, Katja Koeppen, and Arminja N. Kettenbach

Subjects
Proteomics, Hyphal growth, Cancer Research, Mutant, Gene Expression, Yeast and Fungal Models, QH426-470, Pathology and Laboratory Medicine, Biochemistry, Loss of Function Mutation, Gene Expression Regulation, Fungal, Candida albicans, Medicine and Health Sciences, Protein phosphorylation, Post-Translational Modification, Phosphorylation, Genetics (clinical), Candida, Fungal Pathogens, biology, Organic Compounds, Chemistry, Kinase, Transcriptional Control, Monosaccharides, Eukaryota, Cell biology, Phenotypes, Experimental Organism Systems, Medical Microbiology, Physical Sciences, Saccharomyces Cerevisiae, Pathogens, Research Article, Carbohydrates, Hyphae, Mycology, Research and Analysis Methods, Microbiology, Fungal Proteins, Saccharomyces, Model Organisms, Gene Types, DNA-binding proteins, Genetics, Gene Regulation, Kinase activity, Molecular Biology, Microbial Pathogens, Transcription factor, Ecology, Evolution, Behavior and Systematics, Gene Expression Profiling, Organic Chemistry, Organisms, Fungi, Chemical Compounds, Biology and Life Sciences, Proteins, Cyclin-Dependent Kinase 8, biology.organism_classification, Yeast, Regulatory Proteins, Glucose, Purines, Animal Studies, Regulator Genes, Cyclin-dependent kinase 8, Transcription Factors
Abstract

Ssn3, also known as Cdk8, is a member of the four protein Cdk8 submodule within the multi-subunit Mediator complex involved in the co-regulation of transcription. In Candida albicans, the loss of Ssn3 kinase activity affects multiple phenotypes including cellular morphology, metabolism, nutrient acquisition, immune cell interactions, and drug resistance. In these studies, we generated a strain in which Ssn3 was replaced with a functional variant of Ssn3 that can be rapidly and selectively inhibited by the ATP analog 3-MB-PP1. Consistent with ssn3 null mutant and kinase dead phenotypes, inhibition of Ssn3 kinase activity promoted hypha formation. Furthermore, the increased expression of hypha-specific genes was the strongest transcriptional signal upon inhibition of Ssn3 in transcriptomics analyses. Rapid inactivation of Ssn3 was used for phosphoproteomic studies performed to identify Ssn3 kinase substrates associated with filamentation potential. Both previously validated and novel Ssn3 targets were identified. Protein phosphorylation sites that were reduced specifically upon Ssn3 inhibition included two sites in Flo8 which is a transcription factor known to positively regulate C. albicans morphology. Mutation of the two Flo8 phosphosites (threonine 589 and serine 620) was sufficient to increase Flo8-HA levels and Flo8 dependent transcriptional and morphological changes, suggesting that Ssn3 kinase activity negatively regulates Flo8.Under embedded conditions, when ssn3Δ/Δ and efg1Δ/Δ mutants were hyperfilamentous, FLO8 was essential for hypha formation. Previous work has also shown that loss of Ssn3 activity leads to increased alkalinization of medium with amino acids. Here, we show that the ssn3Δ/Δ medium alkalinization phenotype, which is dependent on STP2, a transcription factor involved in amino acid utilization, also requires FLO8 and EFG1. Together, these data show that Ssn3 activity can modulate Flo8 and its direct and indirect interactions in different ways, and underscores the potential importance of considering Ssn3 function in the control of transcription factor activities., Author summary In Candida albicans, Ssn3 kinase activity co-regulates the transcription of numerous genes involved in hyphal growth, metabolism and nutrient acquisition, immune cell interactions, and drug resistance. Using a strain in which Ssn3 could be rapidly and selectively inhibited, we identified both known and novel Ssn3 targets. We identified two phosphosites in Flo8, a regulator of morphology and virulence, that were shown to negatively regulate Flo8 levels and activity. The data and tools presented here will enable a better understanding of how Ssn3 impacts transcriptional and post-transcriptional regulation in order to coordinate processes during physiological and morphological transitions as well as during steady state growth.

Published
2021

10. Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Author

McCartney, DL, Min, JL, Richmond, RC, Lu, AT, Sobczyk, MK, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P-L, Matias-Garcia, PR, Mishra, PP, Nygaard, M, Palviainen, T, Patki, A, Raffield, LM, Ratliff, SM, Richardson, TG, Robinson, O, Soerensen, M, Sun, D, Tsai, P-C, van der Zee, MD, Walker, RM, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugue, P-A, Durda, P, Elliott, HR, Gieger, C, de Geus, EJC, Harris, SE, Hemani, G, Imboden, M, Kahonen, M, Kardia, SLR, Kresovich, JK, Li, S, Lunetta, KL, Mangino, M, Mason, D, McIntosh, AM, Mengel-From, J, Moore, AZ, Murabito, JM, Ollikainen, M, Pankow, JS, Pedersen, NL, Peters, A, Polidoro, S, Porteous, DJ, Raitakari, O, Rich, SS, Sandler, DP, Sillanpaa, E, Smith, AK, Southey, MC, Strauch, K, Tiwari, H, Tanaka, T, Tillin, T, Uitterlinden, AG, van den Berg, DJ, van Dongen, J, Wilson, JG, Wright, J, Yet, I, Arnett, D, Bandinelli, S, Bell, JT, Binder, AM, Boomsma, DI, Chen, W, Christensen, K, Conneely, KN, Elliott, P, Ferrucci, L, Fornage, M, Hagg, S, Hayward, C, Irvin, M, Kaprio, J, Lawlor, DA, Lehtimaki, T, Lohoff, FW, Milani, L, Milne, RL, Probst-Hensch, N, Reiner, AP, Ritz, B, Rotter, JI, Smith, JA, Taylor, JA, van Meurs, JBJ, Vineis, P, Waldenberger, M, Deary, IJ, Relton, CL, Horvath, S, Marioni, RE, McCartney, DL, Min, JL, Richmond, RC, Lu, AT, Sobczyk, MK, Davies, G, Broer, L, Guo, X, Jeong, A, Jung, J, Kasela, S, Katrinli, S, Kuo, P-L, Matias-Garcia, PR, Mishra, PP, Nygaard, M, Palviainen, T, Patki, A, Raffield, LM, Ratliff, SM, Richardson, TG, Robinson, O, Soerensen, M, Sun, D, Tsai, P-C, van der Zee, MD, Walker, RM, Wang, X, Wang, Y, Xia, R, Xu, Z, Yao, J, Zhao, W, Correa, A, Boerwinkle, E, Dugue, P-A, Durda, P, Elliott, HR, Gieger, C, de Geus, EJC, Harris, SE, Hemani, G, Imboden, M, Kahonen, M, Kardia, SLR, Kresovich, JK, Li, S, Lunetta, KL, Mangino, M, Mason, D, McIntosh, AM, Mengel-From, J, Moore, AZ, Murabito, JM, Ollikainen, M, Pankow, JS, Pedersen, NL, Peters, A, Polidoro, S, Porteous, DJ, Raitakari, O, Rich, SS, Sandler, DP, Sillanpaa, E, Smith, AK, Southey, MC, Strauch, K, Tiwari, H, Tanaka, T, Tillin, T, Uitterlinden, AG, van den Berg, DJ, van Dongen, J, Wilson, JG, Wright, J, Yet, I, Arnett, D, Bandinelli, S, Bell, JT, Binder, AM, Boomsma, DI, Chen, W, Christensen, K, Conneely, KN, Elliott, P, Ferrucci, L, Fornage, M, Hagg, S, Hayward, C, Irvin, M, Kaprio, J, Lawlor, DA, Lehtimaki, T, Lohoff, FW, Milani, L, Milne, RL, Probst-Hensch, N, Reiner, AP, Ritz, B, Rotter, JI, Smith, JA, Taylor, JA, van Meurs, JBJ, Vineis, P, Waldenberger, M, Deary, IJ, Relton, CL, Horvath, S, and Marioni, RE

Abstract

BACKGROUND: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. RESULTS: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Published
2021

11. The Whole Atmosphere Community Climate Model Version 6 (WACCM6)

Author

Massachusetts Institute of Technology. Department of Earth, Atmospheric, and Planetary Sciences, Gettelman, A, Mills, MJ, Kinnison, DE, Garcia, RR, Smith, AK, Marsh, DR, Tilmes, S, Vitt, F, Bardeen, CG, McInerny, J, Liu, HL, Solomon, SC, Polvani, LM, Emmons, LK, Lamarque, JF, Richter, JH, Glanville, AS, Bacmeister, JT, Phillips, AS, Neale, RB, Simpson, IR, DuVivier, AK, Hodzic, A, Randel, WJ, Massachusetts Institute of Technology. Department of Earth, Atmospheric, and Planetary Sciences, Gettelman, A, Mills, MJ, Kinnison, DE, Garcia, RR, Smith, AK, Marsh, DR, Tilmes, S, Vitt, F, Bardeen, CG, McInerny, J, Liu, HL, Solomon, SC, Polvani, LM, Emmons, LK, Lamarque, JF, Richter, JH, Glanville, AS, Bacmeister, JT, Phillips, AS, Neale, RB, Simpson, IR, DuVivier, AK, Hodzic, A, and Randel, WJ

Abstract

©2019. American Geophysical Union. All Rights Reserved. The Whole Atmosphere Community Climate Model version 6 (WACCM6) is a major update of the whole atmosphere modeling capability in the Community Earth System Model (CESM), featuring enhanced physical, chemical and aerosol parameterizations. This work describes WACCM6 and some of the important features of the model. WACCM6 can reproduce many modes of variability and trends in the middle atmosphere, including the quasi-biennial oscillation, stratospheric sudden warmings, and the evolution of Southern Hemisphere springtime ozone depletion over the twentieth century. WACCM6 can also reproduce the climate and temperature trends of the 20th century throughout the atmospheric column. The representation of the climate has improved in WACCM6, relative to WACCM4. In addition, there are improvements in high-latitude climate variability at the surface and sea ice extent in WACCM6 over the lower top version of the model (CAM6) that comes from the extended vertical domain and expanded aerosol chemistry in WACCM6, highlighting the importance of the stratosphere and tropospheric chemistry for high-latitude climate variability.

Published
2021

12. SKA2 methylation is associated with decreased prefrontal cortical thickness and greater PTSD severity among trauma-exposed veterans

Author

Massachusetts Institute of Technology. Department of Materials Science and Engineering, Sadeh, N, Spielberg, JM, Logue, MW, Wolf, EJ, Smith, AK, Lusk, J, Hayes, JP, Sperbeck, E, Milberg, WP, McGlinchey, RE, Salat, DH, Carter, WC, Stone, A, Schichman, SA, Humphries, DE, Miller, MW, Massachusetts Institute of Technology. Department of Materials Science and Engineering, Sadeh, N, Spielberg, JM, Logue, MW, Wolf, EJ, Smith, AK, Lusk, J, Hayes, JP, Sperbeck, E, Milberg, WP, McGlinchey, RE, Salat, DH, Carter, WC, Stone, A, Schichman, SA, Humphries, DE, and Miller, MW

Published
2021

13. Long‐Term Variability and Tendencies in Middle Atmosphere Temperature and Zonal Wind From WACCM6 Simulations During 1850–2014

Author

Ramesh, K, Smith, AK, Garcia, RR, Marsh, DR, Sridharan, S, and Kishore Kumar, K

Abstract

Long‐term variability of middle atmosphere temperature (T) and zonal wind (U) is investigated using a three‐member ensemble of historical simulations of NCAR's Whole Atmospheric Community Climate Model latest version 6 (WACCM6) for 1850–2014 (165 years). The model reproduces the climatological features of T and U. The contributions of Quasi Biennial Oscillation (QBO) at 10 and 30 hPa, solar cycle (SC), El Niño‐Southern Oscillation (ENSO), ozone depleting substances (ODS), carbon dioxide (CO2), and stratospheric sulfate aerosol (volcanic eruptions) to change in monthly zonal mean T and U are analyzed using multiple linear regression. The signal due to CO2 increase dominates as a predictor of the net multidecadal global annual mean temperature change at all levels in the middle atmosphere. Contributions from ODS also affect the net multidecadal global mean temperature trend in the stratosphere. Because of similarities in the time evolution of the emissions of CO2 and ODS, the analysis of existing model output cannot accurately separate the attributions of cooling to these two dominant forcing processes. On shorter time scales, solar flux variations are the largest source of variability in the mesosphere while volcanic eruptions are the largest in the stratosphere. In the stratosphere and mesosphere, both QBO and ENSO can significantly impact zonal mean temperature and zonal‐mean zonal wind depending on latitudes, but their impact on the multidecadal global mean temperature trend is very small.

Published
2020

14. Long‐Term Variability and Tendencies in Migrating Diurnal Tide From WACCM6 Simulations During 1850–2014

Author

Ramesh, K, Smith, AK, Garcia, RR, Marsh, DR, Sridharan, S, and Kishore Kumar, K

Abstract

Long‐term variability and tendencies in migrating diurnal tide (DW1) are investigated for the first time using a three‐member ensemble of historical simulations by NCAR's Whole Atmosphere Community Climate Model, latest Version 6 (WACCM6) for 1850–2014 (165 years). The model reproduces the climatological features of the tide in temperature (T), zonal wind (U), and meridional wind (V). The amplitudes peak in the upper mesosphere and lower thermosphere (above ~0.001 hPa) at the equator for T (~10 K) and over 20–30°N and S latitudes for U (~15 m/s) and V (~25 m/s). The contributions of solar cycle (SC), quasi biennial oscillation (QBO) at 10 and 30 hPa, El Niño–Southern Oscillation (ENSO), ozone depleting substances (ODS), carbon dioxide (CO2), and stratospheric sulfate aerosols (volcanic eruptions) to change in annual mean amplitudes are analyzed using multiple linear regression. The tidal amplitudes in three components show a long‐term increase in the upper stratosphere (0.95–10.7 hPa) and the upper mesosphere (0.0001–0.01 hPa), predominantly due to increasing CO2 with a smaller contribution from the trend in ENSO. Interestingly, the global mean tidal amplitude in T decreases sharply after 1950–1960 until 1995 and then increases in association with changes in ODSs. The seasonal differences in tidal responses to the above indices can be as large as the overall signals. All the responses are stronger in the upper mesosphere; however, there is also a pronounced negative response of temperature tide to ODSs over middle to high latitudes around the stratopause (~1 hPa) during all seasons.

Published
2020

15. The Whole Atmosphere Community Climate Model Version 6 (WACCM6)

Author

Gettelman, A, Mills, MJ, Kinnison, DE, Garcia, RR, Smith, AK, Marsh, DR, Tilmes, S, Vitt, F, Bardeen, CG, McInerney, J, Liu, H, Solomon, SC, Polvani, LM, Emmons, LK, Lamarque, J, Richter, JH, Glanville, AS, Bacmeister, JT, Phillips, AS, Neale, RB, Simpson, IR, DuVivier, AK, Hodzic, A, and Randel, WJ

Abstract

The Whole Atmosphere Community Climate Model version 6 (WACCM6) is a major update of the whole atmosphere modeling capability in the Community Earth System Model (CESM), featuring enhanced physical, chemical and aerosol parameterizations. This work describes WACCM6 and some of the important features of the model. WACCM6 can reproduce many modes of variability and trends in the middle atmosphere, including the Quasi‐Biennial Oscillation, Stratospheric Sudden Warmings and the evolution of Southern Hemisphere springtime ozone depletion over the 20th century. WACCM6 can also reproduce the climate and temperature trends of the 20th century throughout the atmospheric column. The representation of the climate has improved in WACCM6, relative to WACCM4. In addition, there are improvements in high latitude climate variability at the surface and sea ice extent in WACCM6 over the lower top version of the model (CAM6) that come from the extended vertical domain and expanded aerosol chemistry in WACCM6, highlighting the importance of the stratosphere and tropospheric chemistry for high latitude climate variability.

Published
2019

22. International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci

Author

Nievergelt, CM, Maihofer, AX, Klengel, T, Atkinson, EG, Chen, C-Y, Choi, KW, Coleman, JR, Dalvie, S, Duncan, LE, Gelernter, J, Levey, DF, Logue, MW, Polimanti, R, Provost, AC, Ratanatharathorn, A, Stein, MB, Torres, K, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Brglum, AD, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Dale, AM, Daly, MJ, Daskalakis, NP, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Dzubur-Kulenovic, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gelaye, B, Geuze, E, Gillespie, C, Uka, AG, Gordon, SD, Guffanti, G, Hammamieh, R, Harnal, S, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Junglen, AG, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, CE, Linnstaedt, SD, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, J, Marmar, C, Martin, AR, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, McLeay, S, Mehta, D, Milberg, WP, Miller, MW, Morey, RA, Morris, CP, Mors, O, Mortensen, PB, Neale, BM, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Ripke, S, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, K, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Sumner, JA, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Wolff, JD, Yehuda, R, Young, RM, Young, KA, Zhao, H, Zoellner, LA, Liberzon, I, Ressler, KJ, Haas, M, Koenen, KC, Nievergelt, CM, Maihofer, AX, Klengel, T, Atkinson, EG, Chen, C-Y, Choi, KW, Coleman, JR, Dalvie, S, Duncan, LE, Gelernter, J, Levey, DF, Logue, MW, Polimanti, R, Provost, AC, Ratanatharathorn, A, Stein, MB, Torres, K, Aiello, AE, Almli, LM, Amstadter, AB, Andersen, SB, Andreassen, OA, Arbisi, PA, Ashley-Koch, AE, Austin, SB, Avdibegovic, E, Babic, D, Baekvad-Hansen, M, Baker, DG, Beckham, JC, Bierut, LJ, Bisson, J, Boks, MP, Bolger, EA, Brglum, AD, Bradley, B, Brashear, M, Breen, G, Bryant, RA, Bustamante, AC, Bybjerg-Grauholm, J, Calabrese, JR, Caldas-de-Almeida, JM, Dale, AM, Daly, MJ, Daskalakis, NP, Deckert, J, Delahanty, DL, Dennis, MF, Disner, SG, Domschke, K, Dzubur-Kulenovic, A, Erbes, CR, Evans, A, Farrer, LA, Feeny, NC, Flory, JD, Forbes, D, Franz, CE, Galea, S, Garrett, ME, Gelaye, B, Geuze, E, Gillespie, C, Uka, AG, Gordon, SD, Guffanti, G, Hammamieh, R, Harnal, S, Hauser, MA, Heath, AC, Hemmings, SMJ, Hougaard, DM, Jakovljevic, M, Jett, M, Johnson, EO, Jones, I, Jovanovic, T, Qin, X-J, Junglen, AG, Karstoft, K-I, Kaufman, ML, Kessler, RC, Khan, A, Kimbrel, NA, King, AP, Koen, N, Kranzler, HR, Kremen, WS, Lawford, BR, Lebois, LAM, Lewis, CE, Linnstaedt, SD, Lori, A, Lugonja, B, Luykx, JJ, Lyons, MJ, Maples-Keller, J, Marmar, C, Martin, AR, Martin, NG, Maurer, D, Mavissakalian, MR, McFarlane, A, McGlinchey, RE, McLaughlin, KA, McLean, SA, McLeay, S, Mehta, D, Milberg, WP, Miller, MW, Morey, RA, Morris, CP, Mors, O, Mortensen, PB, Neale, BM, Nelson, EC, Nordentoft, M, Norman, SB, O'Donnell, M, Orcutt, HK, Panizzon, MS, Peters, ES, Peterson, AL, Peverill, M, Pietrzak, RH, Polusny, MA, Rice, JP, Ripke, S, Risbrough, VB, Roberts, AL, Rothbaum, AO, Rothbaum, BO, Roy-Byrne, P, Ruggiero, K, Rung, A, Rutten, BPF, Saccone, NL, Sanchez, SE, Schijven, D, Seedat, S, Seligowski, A, Seng, JS, Sheerin, CM, Silove, D, Smith, AK, Smoller, JW, Sponheim, SR, Stein, DJ, Stevens, JS, Sumner, JA, Teicher, MH, Thompson, WK, Trapido, E, Uddin, M, Ursano, RJ, van den Heuvel, LL, Van Hooff, M, Vermetten, E, Vinkers, CH, Voisey, J, Wang, Y, Wang, Z, Werge, T, Williams, MA, Williamson, DE, Winternitz, S, Wolf, C, Wolf, EJ, Wolff, JD, Yehuda, R, Young, RM, Young, KA, Zhao, H, Zoellner, LA, Liberzon, I, Ressler, KJ, Haas, M, and Koenen, KC

Abstract

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

Published
2019

25. A DNA methylation biomarker of alcohol consumption

Author

Liu, Chang, Marioni, RE, Hedman, AK, Pfeiffer, L, Tsai, P C, Reynolds, LM, Just, AC, Duan, Q, Boer, Cindy, Tanaka, T, Elks, CE, Aslibekyan, S, Brody, JA, Kuhnel, B, Herder, C, Almli, LM, Zhi, D, Wang, Y, Huan, T, Yao, C, Mendelson, MM, Joehanes, R, Liang, L, Love, SA, Guan, W, Shah, S, Mcrae, AF, Kretschmer, A, Prokisch, H, Strauch, K, Peters, A, Visscher, PM, Wray, NR, Guo, X, Wiggins, KL, Smith, AK, Binder, EB, Ressler, KJ, Irvin, M R, Absher, DM, Hernandez, D, Ferrucci, L, Bandinelli, S, Lohman, K, Ding, J, Trevisi, L, Gustafsson, S, Sandling, JH, Stolk, Lisette, Uitterlinden, André, Yet, I, Castillo-Fernandez, JE, Spector, TD, Schwartz, JD, Vokonas, P, Lind, L, Li, Y, Fornage, M, Arnett, DK, Wareham, NJ, Sotoodehnia, N, Ong, KK, van Meurs, Joyce, Conneely, KN, Baccarelli, AA, Deary, IJ, Bell, JT, North, KE, Liu, Y, Waldenberger, M, London, SJ, Ingelsson, E, Levy, D, Liu, Chang, Marioni, RE, Hedman, AK, Pfeiffer, L, Tsai, P C, Reynolds, LM, Just, AC, Duan, Q, Boer, Cindy, Tanaka, T, Elks, CE, Aslibekyan, S, Brody, JA, Kuhnel, B, Herder, C, Almli, LM, Zhi, D, Wang, Y, Huan, T, Yao, C, Mendelson, MM, Joehanes, R, Liang, L, Love, SA, Guan, W, Shah, S, Mcrae, AF, Kretschmer, A, Prokisch, H, Strauch, K, Peters, A, Visscher, PM, Wray, NR, Guo, X, Wiggins, KL, Smith, AK, Binder, EB, Ressler, KJ, Irvin, M R, Absher, DM, Hernandez, D, Ferrucci, L, Bandinelli, S, Lohman, K, Ding, J, Trevisi, L, Gustafsson, S, Sandling, JH, Stolk, Lisette, Uitterlinden, André, Yet, I, Castillo-Fernandez, JE, Spector, TD, Schwartz, JD, Vokonas, P, Lind, L, Li, Y, Fornage, M, Arnett, DK, Wareham, NJ, Sotoodehnia, N, Ong, KK, van Meurs, Joyce, Conneely, KN, Baccarelli, AA, Deary, IJ, Bell, JT, North, KE, Liu, Y, Waldenberger, M, London, SJ, Ingelsson, E, and Levy, D

Published
2018

26. Prevalence and Outcomes of Breathlessness in Older Adults: A National Population Study

Author

Smith, AK, Currow, DC, Abernethy, AP, Johnson, MJ, Miao, Y, Boscardin, WJ, and Ritchie, CS

Subjects
Aged, 80 and over, Male, Depression, Comorbidity, respiratory system, Anxiety, Risk Assessment, United States, Hospitalization, Dyspnea, Geriatrics, Risk Factors, Chronic Disease, Activities of Daily Living, Prevalence, Humans, Female, Symptom Assessment, Geriatric Assessment, Proportional Hazards Models, Aged
Abstract

© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society Objectives: To determine the prevalence and outcomes of breathlessness in older Americans. Setting: Community-dwelling older adults. Participants: Individuals aged 70 and older in the nationally representative Health and Retirement Study (2008, follow-up through 2012) (N = 3,671; mean age 78). Measurements: Breathlessness was assessed by asking the question, “How often do you become short of breath while awake?” Responses of often or sometimes were considered to represent a level of breathlessness sufficient to warrant clinical attention. The prevalence of breathlessness is described overall and in subpopulations, then rates of associated symptoms, well-being, and health services use of participants who were breathless are compared with rates of those who were not. The risk of decline in activities of daily living (ADLs) and death through 2012 was estimated by creating a multivariable Cox proportional hazards model, adjusting for age, sex, race and ethnicity, and education. Results: Twenty-five percent of participants reported breathlessness. The prevalence of breathlessness was higher in certain subpopulations: chronic lung disease (63%), multimorbidity (≥2 chronic conditions) (45%), current smokers (38%), heart disease (36%), obesity (body mass index ≥30.0 kg/m2) (33%), and education less than high school (32%). Breathlessness was associated with higher rates of depression, anxiety, and severe fatigue; lower ratings of well-being; and higher rates of clinic and emergency department visits and hospitalizations (all P

Published
2016

27. An epigenetic clock for gestational age at birth based on blood methylation data

Author

Knight, AK, Craig, JM, Theda, C, Baekvad-Hansen, M, Bybjerg-Grauholm, J, Hansen, CS, Hollegaard, MV, Hougaard, DM, Mortensen, PB, Weinsheimer, SM, Werge, TM, Brennan, PA, Cubells, JF, Newport, DJ, Stowe, ZN, Cheong, JLY, Dalach, P, Doyle, LW, Loke, YJ, Baccarelli, AA, Just, AC, Wright, RO, Tellez-Rojo, MM, Svensson, K, Trevisi, L, Kennedy, EM, Binder, EB, Iurato, S, Czamara, D, Raikkonen, K, Lahti, JMT, Pesonen, A-K, Kajantie, E, Villa, PM, Laivuori, H, Hamalainen, E, Park, HJ, Bailey, LB, Parets, SE, Kilaru, V, Menon, R, Horvath, S, Bush, NR, LeWinn, KZ, Tylavsky, FA, Conneely, KN, Smith, AK, Knight, AK, Craig, JM, Theda, C, Baekvad-Hansen, M, Bybjerg-Grauholm, J, Hansen, CS, Hollegaard, MV, Hougaard, DM, Mortensen, PB, Weinsheimer, SM, Werge, TM, Brennan, PA, Cubells, JF, Newport, DJ, Stowe, ZN, Cheong, JLY, Dalach, P, Doyle, LW, Loke, YJ, Baccarelli, AA, Just, AC, Wright, RO, Tellez-Rojo, MM, Svensson, K, Trevisi, L, Kennedy, EM, Binder, EB, Iurato, S, Czamara, D, Raikkonen, K, Lahti, JMT, Pesonen, A-K, Kajantie, E, Villa, PM, Laivuori, H, Hamalainen, E, Park, HJ, Bailey, LB, Parets, SE, Kilaru, V, Menon, R, Horvath, S, Bush, NR, LeWinn, KZ, Tylavsky, FA, Conneely, KN, and Smith, AK

Abstract

BACKGROUND: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. RESULTS: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. CONCLUSIONS: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.

Published
2016

28. DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases

Author

Ligthart, Symen, Marzi, C, Aslibekyan, S, Mendelson, MM, Conneely, KN, Tanaka, T, Colicino, E, Waite, LL, Joehanes, R, Guan, WH, Brody, JA, Elks, C, Marioni, R, Jhun, MA, Agha, G, Bressler, J, Ward-Caviness, CK, Chen, BH, Huan, TX, Bakulski, K, Salfati, EL, Wahl, S, Schramm, K, Sha, J, Hernandez, DG, Just, AC, Smith, JA, Sotoodehnia, N, Pilling, LC, Pankow, JS, Tsao, PS, Liu, CY, Zhao, W, Guarrera, S, Michopoulos, VJ, Smith, AK, Peters, Marjolein, Melzer, D, Vokonas, P, Fornage, M, Prokisch, H, Bis, JC, Chu, AY, Herder, Cindy, Grallert, H, Yao, C, Shah, S, Mcrae, AF, Lin, HH, Horvath, S, Fallin, D, Hofman, Bert, Wareham, NJ, Wiggins, KL, Feinberg, AP, Starr, JM, Visscher, PM, Murabito, JM, Kardia, SLR, Absher, DM, Binder, EB, Singleton, AB, Bandinelli, S, Peters, A, Waldenberger, M, Matullo, G, Schwartz, JD, Demerath, EW, Uitterlinden, André, van Meurs, Joyce, Franco Duran, OH, Chen, YDI, Levy, D, Turner, ST, Deary, IJ, Ressler, KJ, Dupuis, J, Ferrucci, L, Ong, KK, Assimes, TL, Boerwinkle, E, Koenig, W, Arnett, DK, Baccarelli, AA, Benjamin, EJ, Dehghan, Abbas, Ligthart, Symen, Marzi, C, Aslibekyan, S, Mendelson, MM, Conneely, KN, Tanaka, T, Colicino, E, Waite, LL, Joehanes, R, Guan, WH, Brody, JA, Elks, C, Marioni, R, Jhun, MA, Agha, G, Bressler, J, Ward-Caviness, CK, Chen, BH, Huan, TX, Bakulski, K, Salfati, EL, Wahl, S, Schramm, K, Sha, J, Hernandez, DG, Just, AC, Smith, JA, Sotoodehnia, N, Pilling, LC, Pankow, JS, Tsao, PS, Liu, CY, Zhao, W, Guarrera, S, Michopoulos, VJ, Smith, AK, Peters, Marjolein, Melzer, D, Vokonas, P, Fornage, M, Prokisch, H, Bis, JC, Chu, AY, Herder, Cindy, Grallert, H, Yao, C, Shah, S, Mcrae, AF, Lin, HH, Horvath, S, Fallin, D, Hofman, Bert, Wareham, NJ, Wiggins, KL, Feinberg, AP, Starr, JM, Visscher, PM, Murabito, JM, Kardia, SLR, Absher, DM, Binder, EB, Singleton, AB, Bandinelli, S, Peters, A, Waldenberger, M, Matullo, G, Schwartz, JD, Demerath, EW, Uitterlinden, André, van Meurs, Joyce, Franco Duran, OH, Chen, YDI, Levy, D, Turner, ST, Deary, IJ, Ressler, KJ, Dupuis, J, Ferrucci, L, Ong, KK, Assimes, TL, Boerwinkle, E, Koenig, W, Arnett, DK, Baccarelli, AA, Benjamin, EJ, and Dehghan, Abbas

Abstract

Background: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. Results: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 x 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 x 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 x 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 x 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58x 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R-2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. Conclusion: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.

Published
2016

29. The transcriptional landscape of age in human peripheral blood

Author

Peters, MJ, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Göring, HHH, Fornage, M, Liu, Y, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Van Rooij, J, Stolk, L, Broer, L, Verbiest, MMPJ, Jhamai, M, Arp, P, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, C, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Völzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, McRae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE, Helmer, Q, Den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, Blangero, J, Peters, MJ, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Göring, HHH, Fornage, M, Liu, Y, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, A, Uitterlinden, AG, Rivadeneira, F, Van Rooij, J, Stolk, L, Broer, L, Verbiest, MMPJ, Jhamai, M, Arp, P, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, C, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Völzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, McRae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE, Helmer, Q, Den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, and Blangero, J

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

30. The transcriptional landscape of age in human peripheral blood

Author

Peters, Marjolein, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Goring, HHH, Fornage, M, Liu, YM, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, van Rooij, J, Stolk, Lisette, Broer, Linda, Verbiest, Michael, Jhamai, M, Arp, Pascal, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, Cindy, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Voelzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, Mcrae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE (Eline), Helmer, Q, den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, Blangero, J, Meulenbelt, I, Ressler, KJ, Yang, Jiaqi, Franke, L, Kettunen, J, Visscher, PM, Neely, GG, Korstanje, R, Hanson, RL, Prokisch, H, Ferrucci, L, Esko, T, Teumer, A, van Meurs, Joyce, Andrew, D, Peters, Marjolein, Joehanes, R, Pilling, LC, Schurmann, C, Conneely, KN, Powell, J, Reinmaa, E, Sutphin, GL, Zhernakova, A, Schramm, K, Wilson, YA, Kobes, S, Tukiainen, T, Ramos, YF, Goring, HHH, Fornage, M, Liu, YM, Gharib, SA, Stranger, BE, De Jager, PL, Aviv, A, Levy, D, Murabito, JM, Munson, PJ, Huan, T, Hofman, Bert, Uitterlinden, André, Rivadeneira, Fernando, van Rooij, J, Stolk, Lisette, Broer, Linda, Verbiest, Michael, Jhamai, M, Arp, Pascal, Metspalu, A, Tserel, L, Milani, L, Samani, NJ, Peterson, P, Kasela, S, Codd, V, Peters, A, Ward-Caviness, CK, Herder, Cindy, Waldenberger, M, Roden, M, Singmann, P, Zeilinger, S, Illig, T, Homuth, G, Grabe, HJ, Voelzke, H, Steil, L, Kocher, T, Murray, A, Melzer, D, Yaghootkar, H, Bandinelli, S, Moses, EK, Kent, JW, Curran, JE, Johnson, MP, Williams-Blangero, S, Westra, HJ, Mcrae, AF, Smith, JA, Kardia, SLR, Hovatta, I, Perola, M, Ripatti, S, Salomaa, V, Henders, AK, Martin, NG, Smith, AK, Mehta, D, Binder, EB, Nylocks, KM, Kennedy, EM, Klengel, T, Ding, J, Suchy-Dicey, AM, Enquobahrie, DA, Brody, J, Rotter, JI, Chen, YDI, Houwing-Duistermaat, J, Kloppenburg, M, Slagboom, PE (Eline), Helmer, Q, den Hollander, W, Bean, S, Raj, T, Bakhshi, N, Wang, QP, Oyston, LJ, Psaty, BM, Tracy, RP, Montgomery, GW, Turner, ST, Blangero, J, Meulenbelt, I, Ressler, KJ, Yang, Jiaqi, Franke, L, Kettunen, J, Visscher, PM, Neely, GG, Korstanje, R, Hanson, RL, Prokisch, H, Ferrucci, L, Esko, T, Teumer, A, van Meurs, Joyce, and Andrew, D

Abstract

Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 individuals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the 'transcriptomic age' of an individual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.

Published
2015

31. When previously expressed wishes conflict with best interests

Author

Smith, AK, Lo, B, and Sudore, R

Subjects
Adult, Male, Lung Neoplasms, Conflict, Hip Fractures, Decision Making, Clinical Sciences, and over, Nursing Homes, Alzheimer Disease, Opthalmology and Optometry, Physicians, 80 and over, Public Health and Health Services, Humans, Psychological, Female, Advance Directives, Aged
Abstract

Rising use of advance directives has made surrogate decision making both easier and harder. In many cases, these directives help guide decision making for patients who have lost decision-making capacity. In some cases, however, directives may conflict with what physicians or surrogates view as what is in the patient's best interest. These conflicts can place substantial emotional and moral burdens on physicians and surrogates, and there is little practical guidance for how to address them. We propose a 5-question framework for untangling the conflict between advance directives and best interests of a patient with a surrogate decision maker: (1) Is the clinical situation an emergency? (2) In view of the patient's values and goals, how likely is it that the benefits of the intervention will outweigh the burdens? (3) How well does the advance directive fit the situation at hand? (4) How much leeway did the patient provide the surrogate for overriding the advance directive? (5) How well does the surrogate represent the patient's best interests? We use 2 clinical cases with contrasting outcomes to demonstrate how this framework can help resolve common dilemmas.

Published
2013

32. Advance care planning and the quality of end-of-life care in older adults

Author

Bischoff, KE, Sudore, R, Miao, Y, Boscardin, WJ, and Smith, AK

Subjects
Male, Terminal Care, Aging, end-of-life, advance directives, and over, Medical and Health Sciences, United States, Advance Care Planning, quality, Clinical Research, Geriatrics, Quality of Life, 80 and over, Humans, Psychological, Female, Adaptation, Aged
Abstract

Objectives To determine whether advance care planning influences quality of end-of-life care. Design In this observational cohort study, Medicare data and survey data from the Health and Retirement Study (HRS) were combined to determine whether advance care planning was associated with quality metrics. Setting The nationally representative HRS. Participants Four thousand three hundred ninety-nine decedent subjects (mean age 82.6 at death, 55% women). Measurements Advance care planning (ACP) was defined as having an advance directive (AD), durable power of attorney (DPOA) or having discussed preferences for end-of-life care with a next of kin. Outcomes included previously reported quality metrics observed during the last month of life (rates of hospital admission, in-hospital death, >14 days in the hospital, intensive care unit admission, >1 emergency department visit, hospice admission, and length of hospice ≤3 days). Results Seventy-six percent of subjects engaged in ACP. Ninety-two percent of ADs stated a preference to prioritize comfort. After adjustment, subjects who engaged in ACP were less likely to die in a hospital (adjusted relative risk (aRR) = 0.87, 95% confidence interval (CI) = 0.80-0.94), more likely to be enrolled in hospice (aRR = 1.68, 95% CI = 1.43-1.97), and less likely to receive hospice for 3 days or less before death (aRR = 0.88, 95% CI = 0.85-0.91). Having an AD, a DPOA or an ACP discussion were each independently associated with a significant increase in hospice use (P

Published
2013

35. Neonatal DNA methylation profile in human twins is specified by a complex interplay between intrauterine environmental and genetic factors, subject to tissue-specific influence

Author

Gordon, L, Joo, JE, Powel, JE, Ollikainen, M, Novakovic, B, Li, X, Andronikos, R, Cruickshank, MN, Conneely, KN, Smith, AK, Alisch, RS, Morley, R, Visscher, PM, Craig, JM, Saffery, R, Gordon, L, Joo, JE, Powel, JE, Ollikainen, M, Novakovic, B, Li, X, Andronikos, R, Cruickshank, MN, Conneely, KN, Smith, AK, Alisch, RS, Morley, R, Visscher, PM, Craig, JM, and Saffery, R

Abstract

Comparison between groups of monozygotic (MZ) and dizygotic (DZ) twins enables an estimation of the relative contribution of genetic and shared and nonshared environmental factors to phenotypic variability. Using DNA methylation profiling of ∼20,000 CpG sites as a phenotype, we have examined discordance levels in three neonatal tissues from 22 MZ and 12 DZ twin pairs. MZ twins exhibit a wide range of within-pair differences at birth, but show discordance levels generally lower than DZ pairs. Within-pair methylation discordance was lowest in CpG islands in all twins and increased as a function of distance from islands. Variance component decomposition analysis of DNA methylation in MZ and DZ pairs revealed a low mean heritability across all tissues, although a wide range of heritabilities was detected for specific genomic CpG sites. The largest component of variation was attributed to the combined effects of nonshared intrauterine environment and stochastic factors. Regression analysis of methylation on birth weight revealed a general association between methylation of genes involved in metabolism and biosynthesis, providing further support for epigenetic change in the previously described link between low birth weight and increasing risk for cardiovascular, metabolic, and other complex diseases. Finally, comparison of our data with that of several older twins revealed little evidence for genome-wide epigenetic drift with increasing age. This is the first study to analyze DNA methylation on a genome scale in twins at birth, further highlighting the importance of the intrauterine environment on shaping the neonatal epigenome.

Published
2012

36. REACTIONS OF THE COORDINATIVELY UNSATURATED CLUSTER [OS3(MU-H)(CO)8(PH2PCH2P(PH)C6H4)] WITH ALKYNES RCCR (R = PH, C6H4ME, ME OR CF3) - CRYSTAL-STRUCTURES OF [OS3(CO)8(MU-3-ETA-2(PARALLEL-TO)-RC2R)(PH2PCH2PPH2)] (R = ME OR CF3) AND ELECTROCHEMICAL-BEHAVIOR OF TRIOSMIUM ALKYNE CLUSTERS

Author

Brown, Mp, Dolby, Pa, Harding, Mm, Mathews, Aj, Smith, Ak, Osella, D, Arbrun, M, Gobetto, Roberto, Raithby, Pr, and Zanello, P.

Subjects
PLATINUM, COORDINATION, REDUCTION, CARBONYL CLUSTERS, COMPLEXES, REORIENTATION, REACTIVITY, ELECTRODES, MERCURY, MOIETY
Published
1993

39. Farletuzumab, an anti-folate receptor α antibody, does not block binding of folate or anti-folates to receptor nor does it alter the potency of anti-folates in vitro.

Author

Kamen BA, Smith AK, Kamen, B A, and Smith, A K

Abstract

Purpose: Folate is a cofactor in the synthesis of purines and pyrimidines; folate analogs are potent cytotoxic drugs. Folate receptor alpha (FRα), a protein-mediating cellular accumulation of folate (and anti-folates), has limited expression in normal tissues and is overexpressed by numerous carcinomas. Limited distribution and high affinity for folic acid have resulted in the development of antibodies or the use of folic acid coupled to toxins or radionuclides as therapeutic and imaging agents. Farletuzumab is an anti-FRα antibody in clinical trials for ovarian and non-small cell lung cancers. Our goal was to evaluate the effect of farletuzumab on binding and uptake of folates and anti-folates and the potency of anti-folates in vitro.Methods: Direct binding and uptake of radiolabeled folates and anti-folates and the assessments of drug concentration of drug that inhibited cell growth 50 % (IC(50)) in vitro in the presence or absence of antibody.Results: Farletuzumab did not block membrane binding of radiolabeled folic acid, 5-methyltetrahydrofolate, pemetrexed, and other anti-folates; folic acid blocked >95 %. Farletuzumab had a minimal effect on the cytoplasmic accumulation of 5-methyltetrahydrofolate or pemetrexed; folic acid had a considerable but variable effect on the different cell lines. As a single agent, farletuzumab did not affect cell viability or the IC(50) of pemetrexed and other anti-folates in vitro.Conclusions: Farletuzumab does not block FRα binding of folates and anti-folates, minimally retards folate delivery via FRα-mediated transport, and minimally retards the growth of cells in vitro. Concomitant use of farletuzumab and pemetrexed is not contraindicated. [ABSTRACT FROM AUTHOR]

Published
2012
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40. "Knowing is better": preferences of diverse older adults for discussing prognosis.

Author

Ahalt C, Walter LC, Yourman L, Eng C, Pérez-Stable EJ, Smith AK, Ahalt, Cyrus, Walter, Louise C, Yourman, Lindsey, Eng, Catherine, Pérez-Stable, Eliseo J, and Smith, Alexander K

Abstract

Background: Prognosis is critical in individualizing care for older adults with late life disability. Evidence suggests that preferences for prognostic information may be culturally determined. Yet little is known about the preferences of diverse elders for discussing prognosis.Objective: To determine the preferences for discussing prognosis of a diverse sample of older adults with late-life disability.Design& Participants: We interviewed 60 older adults with mean age 78 and mean 2.5 Activities of Daily Living dependencies. Participants were recruited from San Francisco's On Lok program, the first Program of All-inclusive Care for the Elderly (PACE). Participants were interviewed in English, Spanish, and Cantonese, and responded to scenarios in which their doctors estimated they had 5 years and 1 year left to live. Open-ended questions explored the reasons for their responses. Results were analyzed qualitatively using grounded theory.Key Results: Sixty-five percent of participants wanted to discuss the prognosis if their doctor estimated they had <5 years to live and 75% if the estimate was <1 year. Three themes were prominent among patients who wanted to discuss prognosis: to prepare, to make the most of the life they had left, and to make medical or health-related decisions. Those who preferred not to discuss prognosis described emotional difficulty, the uncertainty of prognosis, or that it would not be useful. Nearly all participants said that doctors should not make assumptions based on race or ethnicity, though differences between ethnic groups emerged.Conclusions: Most patients in this diverse sample of disabled elders were interested in discussing prognosis, while a substantial minority was not. Among those participants who preferred to discuss prognosis, many said that prognostic information would be important as they made difficult medical and personal decisions in late-life. Clinicians should inquire about preferences for discussing prognosis before sharing prognostic estimates. [ABSTRACT FROM AUTHOR]

Published
2012
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41. Prognostic indices for older adults: a systematic review.

Author

Yourman LC, Lee SJ, Schonberg MA, Widera EW, Smith AK, Yourman, Lindsey C, Lee, Sei J, Schonberg, Mara A, Widera, Eric W, and Smith, Alexander K

Abstract

Context: To better target services to those who may benefit, many guidelines recommend incorporating life expectancy into clinical decisions.Objective: To assess the quality and limitations of prognostic indices for mortality in older adults through systematic review.Data Sources: We searched MEDLINE, EMBASE, Cochrane, and Google Scholar from their inception through November 2011.Study Selection: We included indices if they were validated and predicted absolute risk of mortality in patients whose average age was 60 years or older. We excluded indices that estimated intensive care unit, disease-specific, or in-hospital mortality.Data Extraction: For each prognostic index, we extracted data on clinical setting, potential for bias, generalizability, and accuracy.Results: We reviewed 21,593 titles to identify 16 indices that predict risk of mortality from 6 months to 5 years for older adults in a variety of clinical settings: the community (6 indices), nursing home (2 indices), and hospital (8 indices). At least 1 measure of transportability (the index is accurate in more than 1 population) was tested for all but 3 indices. By our measures, no study was free from potential bias. Although 13 indices had C statistics of 0.70 or greater, none of the indices had C statistics of 0.90 or greater. Only 2 indices were independently validated by investigators who were not involved in the index's development.Conclusion: We identified several indices for predicting overall mortality in different patient groups; future studies need to independently test their accuracy in heterogeneous populations and their ability to improve clinical outcomes before their widespread use can be recommended. [ABSTRACT FROM AUTHOR]

Published
2012
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43. Emergency department experiences of acutely symptomatic patients with terminal illness and their family caregivers.

Author

Smith AK, Schonberg MA, Fisher J, Pallin DJ, Block SD, Forrow L, McCarthy EP, Smith, Alexander K, Schonberg, Mara A, Fisher, Jonathan, Pallin, Daniel J, Block, Susan D, Forrow, Lachlan, and McCarthy, Ellen P

Abstract

Context: Despite increased focus on improving palliative care in the emergency department (ED), there is little research on how to best address the specific needs of this patient population.Objectives: To better understand the experiences of acutely symptomatic patients seen in the ED.Methods: Using in-person semi-structured interviews, we explored the attitudes, experiences, and beliefs of 14 patients and seven family caregivers on the inpatient palliative care consult service, who had been admitted through the ED at two academic medical centers. We used a grounded theory approach to code responses. Transcripts were coded by a palliative medicine physician, an emergency medicine physician, and a general internist. Discrepancies were resolved by consensus. Coded sections were iteratively reviewed for interpretation, and concepts were collapsed into themes.Results: Five distinct themes emerged: 1) unprepared for managing symptoms at home; 2) uncertainty and anxiety; 3) communication is essential; 4) mixed experiences with symptom management; and 5) conflicting perspectives about the purpose of palliative care clinicians in the ED.Conclusion: Patients and caregivers identified systems, communication, and clinical issues in ED care that should be a focus for future research. [ABSTRACT FROM AUTHOR]

Published
2010
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44. Palliative care for Latino patients and their families: whenever we prayed, she wept.

Author

Smith AK, Sudore RL, Pérez-Stable EJ, Smith, Alexander K, Sudore, Rebecca L, and Pérez-Stable, Eliseo J

Abstract

Latinos account for 15% of the US population, a proportion projected to grow to 30% by the year 2050. Although there is tremendous diversity within this community, commonalities of language, beliefs, attitudes, and behaviors unite Latinos, making them more similar than different. Differences by national origin, although important, are attenuated when immigrants come to the United States, dominated by an English-language, Anglo-centric culture. For non-Latino and non-Spanish-speaking clinicians, communication barriers and cultural misunderstandings can impede the care of dying Latino patients and their families. We present the case of a young, pregnant, Spanish-speaking woman from Central America diagnosed with a fatal leukemia. As illustrated by this case, Latino immigrants face a number of external challenges to optimal end-of-life care: (1) geographic distance as well as political and economic realities often separate patients from their valued families; (2) undocumented immigrants are frequently uninsured and fear of deportation may create a barrier to accessing health services; (3) language and literacy barriers; and (4) concerns about discrimination. Other Latino issues that may be more pronounced in end-of-life settings include cultural themes and religious and spiritual influences. We recommend that professional interpreters must be used for discussions about goals of care with Spanish-speaking patients and families or when negotiating conflict between the patient, family, and the health care team. Concrete suggestions are provided for clinicians in working with interpreters, eliciting culturally based attitudes and beliefs, and implementing universal strategies for clear health communication. [ABSTRACT FROM AUTHOR]

Published
2009
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46. On being fired: experiences of patient-initiated termination of the patient-physician relationship in palliative medicine.

Author

Smith AK, Buss MK, Giansiracusa DF, and Block SD

Abstract

Background: Being ;;fired'' by a patient is an uncomfortable, distressing, and awkward experience for most clinicians. Palliative care clinicians may be at increased risk of termination of the patient-physician relationship for a variety of reasons. Little has been written about the experience of patient-initiated termination of the patient-physician relationship, and to our knowledge, nothing has been written that is specific to palliative care. Objective: To discuss the experience of termination, offer a framework for learning from and coping with the experience, and make recommendations for how to meet patients' needs after the termination. Design: Case study and conceptual analysis of three cases from the experience of a palliative care fellow. Conclusions: The experience of patient-initiated termination of the patient-physician relationship can raise issues of rejection and self-doubt in the palliative care clinician, but can also provide important opportunities for growth, reflection, and learning. In some cases, re-connecting with the patients' families may be appropriate and beneficial for both the clinician and family. [ABSTRACT FROM AUTHOR]

Published
2007
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