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Wu, Ann

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Wu, Ann
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    Access to Guideline-Recommended Pharmacogenomic Tests for Cancer Treatments: Experience of Providers and Patients
    (MDPI, 2017) Wu, Ann; Mazor, Kathleen M.; Ceccarelli, Rachel; Loomer, Stephanie; Lu, Christine
    Genomic tests are the fastest growing sector in medicine and medical science, yet there remains a dearth of research on access to pharmacogenomic tests and medications. The objective of this study is to explore providers’ and patients’ experiences and views on test access as well as strategies used for gaining access. We interviewed clinicians who prescribed medications that should be guided by pharmacogenomic testing and patients who received those prescriptions. We organized the themes into the four dimensions suggested by the World Health Organization framework on access to medications and health technologies. Guideline-recommended pharmacogenomic tests for cancer care are generally available, although the timeliness of return of test results is sometimes suboptimal. Accessibility of pharmacogenomic tests is made challenging by the process of ordering pharmacogenomic tests, which is time-consuming. Affordability is a barrier to some patients as expressed by both providers and patients, who noted that the cost of pharmacogenomic tests and medications is high. Acceptability of the tests is high as both providers and patients view the tests positively. Understanding challenges to accessing pharmacogenomic tests will allow policymakers to develop policies that streamline access to genomics-based technologies to improve population health.
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    A polymorphism in HLA-G modifies statin benefit in asthma
    (2014) Naidoo, Devesh; Wu, Ann; Brilliant, Murray H; Denny, Joshua; Ingram, Christie; Kitchner, Terrie E; Linneman, James G; McGeachie, Michael; Roden, Dan M; Shaffer, Christian M; Shah, Anushi; Weeke, Peter; Weiss, Scott; Xu, Hua; Medina, Marisa W
    Several reports have shown that statin treatment benefits patients with asthma, however inconsistent effects have been observed. The mir-152 family (148a, 148b and 152) has been implicated in asthma. These microRNAs suppress HLA-G expression, and rs1063320, a common SNP in the HLA-G 3’UTR which is associated with asthma risk, modulates miRNA binding. We report that statins up-regulate mir-148b and 152, and affect HLA-G expression in an rs1063320 dependent fashion. In addition, we found that individuals who carried the G minor allele of rs1063320 had reduced asthma related exacerbations (emergency department visits, hospitalizations or oral steroid use) compared to non-carriers (p=0.03) in statin users ascertained in the Personalized Medicine Research Project at the Marshfield Clinic (n=421). These findings support the hypothesis that rs1063320 modifies the effect of statin benefit in asthma, and thus may contribute to variation in statin efficacy for the management of this disease.
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    CMTR1 is associated with increased asthma exacerbations in patients taking inhaled corticosteroids
    (John Wiley and Sons Inc., 2015) Dahlin, Amber; Denny, Joshua; Roden, Dan M.; Brilliant, Murray H.; Ingram, Christie; Kitchner, Terrie E.; Linneman, James G.; Shaffer, Christian M.; Weeke, Peter; Xu, Hua; Kubo, Michiaki; Tamari, Mayumi; Clemmer, George L.; Ziniti, John; McGeachie, Michael; Tantisira, Kelan; Weiss, Scott; Wu, Ann
    Abstract Inhaled corticosteroids (ICS) are the most effective controller medications for asthma, and variability in ICS response is associated with genetic variation. Despite ICS treatment, some patients with poor asthma control experience severe asthma exacerbations, defined as a hospitalization or emergency room visit. We hypothesized that some individuals may be at increased risk of asthma exacerbations, despite ICS use, due to genetic factors. A GWAS of 237,726 common, independent markers was conducted in 806 Caucasian asthmatic patients from two population‐based biobanks: BioVU, at Vanderbilt University Medical Center (VUMC) in Tennessee (369 patients), and Personalized Medicine Research Project (PMRP) at the Marshfield Clinic in Wisconsin (437 patients). Using a case–control study design, the association of each SNP locus with the outcome of asthma exacerbations (defined as asthma‐related emergency department visits or hospitalizations concurrent with oral corticosteroid use), was evaluated for each population by logistic regression analysis, adjusting for age, gender and the first four principal components. A meta‐analysis of the results was conducted. Validation of expression of selected candidate genes was determined by evaluating an independent microarray expression data set. Our study identified six novel SNPs associated with differential risk of asthma exacerbations (P < 10−05). The top GWAS result, rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03–1.11; joint P = 2.3 × 10−06). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, while the remaining four SNPs (rs4271056, rs6467778, rs2691529, and rs9303988) were associated with decreased risk. Three SNPs (rs2395672, rs6467778, and rs2691529) were present in three genes: CMTR1, TRIM24 and MAGI2. The CMTR1 mRNA transcript was significantly differentially expressed in nasal lavage samples from asthmatics during acute exacerbations, suggesting potential involvement of this gene in the development of this phenotype. We show that genetic variability may contribute to asthma exacerbations in patients taking ICS. Furthermore, our studies implicate CMTR1 as a novel candidate gene with potential roles in the pathogenesis of asthma exacerbations.
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    Proceedings from the 9th annual conference on the science of dissemination and implementation: Washington, DC, USA. 14-15 December 2016
    (BioMed Central, 2017) Chambers, David; Simpson, Lisa; Neta, Gila; Schwarz, Ulrica von Thiele; Percy-Laurry, Antoinette; Aarons, Gregory A.; Brownson, Ross; Vogel, Amanda; Stirman, Shannon Wiltsey; Sherr, Kenneth; Sturke, Rachel; Norton, Wynne E.; Varley, Allyson; Vinson, Cynthia; Klesges, Lisa; Heurtin-Roberts, Suzanne; Massoud, M. Rashad; Kimble, Leighann; Beck, Arne; Neely, Claire; Boggs, Jennifer; Nichols, Carmel; Wan, Wen; Staab, Erin; Laiteerapong, Neda; Moise, Nathalie; Shah, Ravi; Essock, Susan; Handley, Margaret; Jones, Amy; Carruthers, Jay; Davidson, Karina; Peccoralo, Lauren; Sederer, Lloyd; Molfenter, Todd; Scudder, Ashley; Taber-Thomas, Sarah; Schaffner, Kristen; Herschell, Amy; Woodward, Eva; Pitcock, Jeffery; Ritchie, Mona; Kirchner, JoAnn; Moore, Julia E.; Khan, Sobia; Rashid, Shusmita; Park, Jamie; Courvoisier, Melissa; Straus, Sharon; Blonigen, Daniel; Rodriguez, Allison; Manfredi, Luisa; Nevedal, Andrea; Rosenthal, Joel; Smelson, David; Timko, Christine; Stadnick, Nicole; Regan, Jennifer; Barnett, Miya; Lau, Anna; Brookman-Frazee, Lauren; Guerrero, Erick; Fenwick, Karissa; Kong, Yinfei; Aarons, Gregory; Lengnick-Hall, Rebecca; Henwood, Benjamin; Sayer, Nina; Rosen, Craig; Orazem, Robert; Smith, Brandy; Zimmerman, Lindsey; Lounsbury, David; Kimerling, Rachel; Trafton, Jodie A.; Lindley, Steven; Bhargava, Rahul; Roberts, Hal; Gibson, Laura; Escobar, Gabriel J.; Liu, Vincent; Turk, Benjamin; Ragins, Arona; Kipnis, Patricia; Gruszkowski, Ashley Ketterer; Kennedy, Michael W.; Drobek, Emily Rentschler; Turgeman, Lior; Milicevic, Aleksandra Sasha; Hubert, Terrence L.; Myaskovsky, Larissa; Tjader, Youxu C.; Monte, Robert J.; Sapnas, Kathryn G.; Ramly, Edmond; Lauver, Diane R; Bartels, Christie M; Elnahal, Shereef; Ippolito, Andrea; Peabody, Hillary; Clancy, Carolyn; Cebul, Randall; Love, Thomas; Einstadter, Douglas; Bolen, Shari; Watts, Brook; Yakovchenko, Vera; Park, Angela; Lukesh, William; Miller, Donald R.; Thornton, David; Drainoni, Mari-Lynn; Gifford, Allen L.; Smith, Shawna; Kyle, Julia; Bauer, Mark; Eisenberg, Daniel; Liebrecht, Celeste; Barbaresso, Michelle; Kilbourne, Amy; Park, Elyse; Perez, Giselle; Ostroff, Jamie; Greene, Sarah; Parchman, Michael; Austin, Brian; Larson, Eric; Ferreri, Stefanie; Shea, Chris; Smith, Megan; Turner, Kea; Bacci, Jennifer; Bigham, Kyle; Curran, Geoffrey; Frail, Caity; Hamata, Cory; Jankowski, Terry; Lantaff, Wendy; McGivney, Melissa Somma; Snyder, Margie; McCullough, Megan; Gillespie, Chris; Petrakis, Beth Ann; Jones, Ellen; Lukas, Carol VanDeusen; Rose, Adam; Shoemaker, Sarah J.; Thomas, Jeremy; Teeter, Benjamin; Swan, Holly; Balamurugan, Appathurai; Lane-Fall, Meghan; Beidas, Rinad; Di Taranti, Laura; Buddai, Sruthi; Hernandez, Enrique Torres; Watts, Jerome; Fleisher, Lee; Barg, Frances; Miake-Lye, Isomi; Olmos, Tanya; Chuang, Emmeline; Rodriguez, Hector; Kominski, Gerald; Yano, Becky; Shortell, Stephen; Hook, Mary; Fleisher, Linda; Fiks, Alexander; Halkyard, Katie; Gruver, Rachel; Sykes, Emily; Vesco, Kimberly; Beadle, Kate; Bulkley, Joanna; Stoneburner, Ashley; Leo, Michael; Clark, Amanda; Smith, Joan; Smyser, Christopher; Wolf, Maggie; Trivedi, Shamik; Hackett, Brian; Rao, Rakesh; Cole, F. Sessions; McGonigle, Rose; Donze, Ann; Proctor, Enola; Mathur, Amit; Gakidou, Emmanuela; Gloyd, Stephen; Audet, Carolyn; Salato, Jose; Vermund, Sten; Amico, Rivet; Smith, Stephanie; Nyirandagijimana, Beatha; Mukasakindi, Hildegarde; Rusangwa, Christian; Franke, Molly; Raviola, Giuseppe; Cummings, Matthew; Goldberg, Elijah; Mwaka, Savio; Kabajaasi, Olive; Cattamanchi, Adithya; Katamba, Achilles; Jacob, Shevin; Kenya-Mugisha, Nathan; Davis, J. Lucian; Reed, Julie; Ramaswamy, Rohit; Parry, Gareth; Sax, Sylvia; Kaplan, Heather; Huang, Keng-yen; Cheng, Sabrina; Yee, Susan; Hoagwood, Kimberly; McKay, Mary; Shelley, Donna; Ogedegbe, Gbenga; Brotman, Laurie Miller; Kislov, Roman; Humphreys, John; Harvey, Gill; Wilson, Paul; Lieberthal, Robert; Payton, Colleen; Sarfaty, Mona; Valko, George; Bolton, Rendelle; Hartmann, Christine; Mueller, Nora; Holmes, Sally K.; Bokhour, Barbara; Ono, Sarah; Crabtree, Benjamin; Gordon, Leah; Miller, William; Balasubramanian, Bijal; Solberg, Leif; Cohen, Deborah; McGraw, Kate; Blatt, Andrew; Pittman, Demietrice; Kales, Helen; Berlowitz, Dan; Hudson, Teresa; Helfrich, Christian; Finley, Erin; Garcia, Ashley; Rosen, Kristen; Tami, Claudina; McGeary, Don; Pugh, Mary Jo; Potter, Jennifer Sharpe; Stryczek, Krysttel; Au, David; Zeliadt, Steven; Sayre, George; Leeman, Jennifer; Myers, Allison; Grant, Jennifer; Wangen, Mary; Queen, Tara; Morshed, Alexandra; Dodson, Elizabeth; Tabak, Rachel; Brownson, Ross C.; Sheldrick, R. Chris; Mackie, Thomas; Hyde, Justeen; Leslie, Laurel; Yanovitzky, Itzhak; Weber, Matthew; Gesualdo, Nicole; Kristensen, Teis; Stanick, Cameo; Halko, Heather; Dorsey, Caitlin; Powell, Byron; Weiner, Bryan; Lewis, Cara; Carreno, Patricia; Mallard, Kera; Masina, Tasoula; Monson, Candice; Swindle, Taren; Patterson, Zachary; Whiteside-Mansell, Leanne; Hanson, Rochelle; Saunders, Benjamin; Schoenwald, Sonja; Moreland, Angela; Birken, Sarah; Presseau, Justin; Ganz, David; Mittman, Brian; Delevan, Deborah; Hill, Jennifer N.; Locatelli, Sara; Fix, Gemmae; Solomon, Jeffrey; Lavela, Sherri L.; Scott, Victoria; Scaccia, Jonathan; Alia, Kassy; Skiles, Brittany; Wandersman, Abraham; Sales, Anne; Roberts, Megan; Kennedy, Amy; Khoury, Muin J.; Sperber, Nina; Orlando, Lori; Carpenter, Janet; Cavallari, Larisa; Denny, Joshua; Elsey, Amanda; Fitzhenry, Fern; Guan, Yue; Horowitz, Carol; Johnson, Julie; Madden, Ebony; Pollin, Toni; Pratt, Victoria; Rakhra-Burris, Tejinder; Rosenman, Marc; Voils, Corrine; Weitzel, Kristin; Wu, Ryanne; Damschroder, Laura; Lu, Christine; Ceccarelli, Rachel; Mazor, Kathleen M.; Wu, Ann; Rahm, Alanna Kulchak; Buchanan, Adam H.; Schwartz, Marci; McCormick, Cara; Manickam, Kandamurugu; Williams, Marc S.; Murray, Michael F.; Escoffery, Ngoc-Cam; Lebow-Skelley, Erin; Udelson, Hallie; Böing, Elaine; Fernandez, Maria E.; Wood, Richard J.; Mullen, Patricia Dolan; Parekh, Jenita; Caldas, Valerie; Stuart, Elizabeth A.; Howard, Shalynn; Thomas, Gilo; Jennings, Jacky M.; Torres, Jennifer; Markham, Christine; Shegog, Ross; Peskin, Melissa; Rushing, Stephanie Craig; Gaston, Amanda; Gorman, Gwenda; Jessen, Cornelia; Williamson, Jennifer; Ward, Dianne; Vaughn, Amber; Morris, Ellie; Mazzucca, Stephanie; Burney, Regan; Ramanadhan, Shoba; Minsky, Sara; Martinez-Dominguez, Vilma; Viswanath, Kasisomayajula; Barker, Megan; Fahim, Myra; Ebnahmady, Arezoo; Dragonetti, Rosa; Selby, Peter; Farrell, Margaret; Tompkins, Jordan; Norton, Wynne; Rapport, Kaelin; Hargreaves, Margaret; Lee, Rebekka; Kruse, Gina; Deutsch, Charles; Lanier, Emily; Gray, Ashley; Leppin, Aaron; Christiansen, Lori; Schaepe, Karen; Egginton, Jason; Branda, Megan; Gaw, Charlene; Dick, Sara; Montori, Victor; Shah, Nilay; Korn, Ariella; Hovmand, Peter; Fullerton, Karen; Zoellner, Nancy; Hennessy, Erin; Tovar, Alison; Hammond, Ross; Economos, Christina; Kay, Christi; Gazmararian, Julie; Vall, Emily; Cheung, Patricia; Franks, Padra; Barrett-Williams, Shannon; Weiss, Paul; Hamilton, Erica; Marques, Luana; Dixon, Louise; Ahles, Emily; Valentine, Sarah; Shtasel, Derri; Parra-Cardona, Ruben; Northridge, Mary; Kavathe, Rucha; Zanowiak, Jennifer; Wyatt, Laura; Singh, Hardayal; Islam, Nadia; Monteban, Madalena; Freedman, Darcy; Bess, Kimberly; Walsh, Colleen; Matlack, Kristen; Flocke, Susan; Baily, Heather; Harden, Samantha; Ramalingam, NithyaPriya; Gold, Rachel; Cottrell, Erika; Hollombe, Celine; Dambrun, Katie; Bunce, Arwen; Middendorf, Mary; Dearing, Marla; Cowburn, Stuart; Mossman, Ned; Melgar, Gerry; Hopfer, Suellen; Hecht, Michael; Ray, Anne; Miller-Day, Michelle; BeLue, Rhonda; Zimet, Greg; Nelson, Eve-Lynn; Kuhlman, Sandy; Doolittle, Gary; Krebill, Hope; Spaulding, Ashley; Levin, Theodore; Sanchez, Michael; Landau, Molly; Escobar, Patricia; Minian, Nadia; Noormohamed, Aliya; Zawertailo, Laurie; Baliunas, Dolly; Giesbrecht, Norman; Le Foll, Bernard; Samokhvalov, Andriy; Meisel, Zachary; Polsky, Daniel; Schackman, Bruce; Mitchell, Julia; Sevarino, Kaitlyn; Gimbel, Sarah; Mwanza, Moses; Nisingizwe, Marie Paul; Michel, Catherine; Hirschhorn, Lisa; Choudhary, Mahrukh; Thonduparambil, Della; Meissner, Paul; Pinnock, Hilary; Barwick, Melanie; Carpenter, Christopher; Eldridge, Sandra; Grandes-Odriozola, Gonzalo; Griffiths, Chris; Rycroft-Malone, Jo; Murray, Elizabeth; Patel, Anita; Sheikh, Aziz; Taylor, Stephanie J. C.; Guilliford, Martin; Pearce, Gemma; Korngiebel, Diane; West, Kathleen; Burke, Wylie; Hannon, Peggy; Harris, Jeffrey; Hammerback, Kristen; Kohn, Marlana; Chan, Gary K. C.; Mafune, Riki; Parrish, Amanda; Beresford, Shirley; Pike, K. Joanne; Shelton, Rachel; Jandorf, Lina; Erwin, Deborah; Charles, Thana-Ashley; Baldwin, Laura-Mae; Ike, Brooke; Fickel, Jacqueline; Lind, Jason; Cowper, Diane; Fleming, Marguerite; Sadler, Amy; Dye, Melinda; Katzburg, Judith; Ong, Michael; Tubbesing, Sarah; Simmons, Molly; Harnish, Autumn; Gabrielian, Sonya; McInnes, Keith; Smith, Jeffrey; Ferrand, John; Torres, Elisa; Green, Amy; Bradbury, Angela R.; Patrick-Miller, Linda J.; Egleston, Brian L.; Domchek, Susan M.; Olopade, Olufunmilayo I.; Hall, Michael J.; Daly, Mary B.; Grana, Generosa; Ganschow, Pamela; Fetzer, Dominique; Brandt, Amanda; Chambers, Rachelle; Clark, Dana F.; Forman, Andrea; Gaber, Rikki S.; Gulden, Cassandra; Horte, Janice; Long, Jessica; Lucas, Terra; Madaan, Shreshtha; Mattie, Kristin; McKenna, Danielle; Montgomery, Susan; Nielsen, Sarah; Powers, Jacquelyn; Rainey, Kim; Rybak, Christina; Seelaus, Christina; Stoll, Jessica; Stopfer, Jill; Yao, Xinxin Shirley; Savage, Michelle; Miech, Edward; Damush, Teresa; Rattray, Nicholas; Myers, Jennifer; Homoya, Barbara; Winseck, Kate; Klabunde, Carrie; Langer, Deb; Aggarwal, Avi; Neilson, Elizabeth; Gunderson, Lara; Gardner, Marla; O’Sulleabhain, Liam; Kroenke, Candyce
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    The metabolomics of asthma control: a promising link between genetics and disease
    (John Wiley & Sons, Ltd, 2015) McGeachie, Michael; Dahlin, Amber; Qiu, Weiliang; Croteau-Chonka, Damien; Savage, Jessica; Wu, Ann; Wan, Emily; Sordillo, Joanne; Al-Garawi, Amal; Martinez, Fernando D; Strunk, Robert C; Lemanske, Robert F; Liu, Andrew H; Raby, Benjamin; Weiss, Scott; Clish, Clary B; Lasky-Su, Jessica
    Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative “omics” approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), ­ using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites—monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control.
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    Inhaled corticosteroid treatment modulates ZNF432 gene variant’s effect on bronchodilator response in asthmatics
    (Elsevier BV, 2014) Wu, Ann; Himes, Blanca; Lasky-Su, Jessica; Litonjua, Augusto A.; Peters, Stephen P.; Lima, John; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Qiu, Weiliang; Weiss, Scott; Tantisira, Kelan
    Background: Single nucleotide polymorphisms (SNPs) influence a patient's response to inhaled corticosteroids and β2-agonists, and the effect of treatment with inhaled corticosteroids is synergistic with the effect of β2-agonists. We hypothesized that use of inhaled corticosteroids could influence the effect of SNPs associated with bronchodilator response. Objective: To assess whether, among asthma subjects, the association of SNPs with bronchodilator response is different between those treated with inhaled corticosteroids vs. those on placebo. Methods: A genome-wide association analysis was conducted using 581 white subjects from the Childhood Asthma Management Program (CAMP). Using data for 449,540 SNPs, we conducted a gene by environment analysis in PLINK with inhaled corticosteroid treatment as the environmental exposure and bronchodilator response as the outcome measure. We attempted to replicate the top 12 SNPs in the Leukotriene Modifier Or Corticosteroid or Corticosteroid-Salmeterol (LOCCS) Trial. Results: The combined P-value for the CAMP and LOCCS populations was 4.81E-08 for rs3752120, which is located in the zinc finger protein gene ZNF432, and has unknown function. Conclusions: Inhaled corticosteroids appear to modulate the association of bronchodilator response with variant(s) in the ZNF432 gene among adults and children with asthma. Clinical Implications: Clinicians who treat asthma patients with inhaled corticosteroids should be aware that the patient's genetic makeup likely influences response as measured in lung function. Capsule Summary: Our study suggests that inhaled corticosteroids could influence the effect of multiple SNPs associated with bronchodilator response across the genome.
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    Pharmacogenomic test that predicts response to inhaled corticosteroids in adults with asthma likely to be cost-saving
    (Future Medicine Ltd, 2015) Wu, Ann; Gay, Charlene; Rett, Melisa D.; Stout, Natasha; Weiss, Scott; Fuhlbrigge, Anne
    Aim: To identify the clinical and economic circumstances under which a pharmacogenomic test that predicts response to inhaled corticosteroids might be a cost-effective option for individuals with asthma. Materials & methods: We synthesized published data on clinical and economic outcomes to project 10-year costs, quality-adjusted life-years and cost–effectiveness of pharmacogenomic testing for inhaled corticosteroid response. We assumed the pharmacogenomic test cost was $500 with a sensitivity and specificity of 84 and 98%, respectively. These were varied in sensitivity analyses. Results: Both strategies, pharmacogenomic testing for inhaled corticosteroid response and no testing conferred 7.1 quality-adjusted life-years. Compared with no testing, pharmacogenomic testing costs less. Conclusion: Pharmacogenomic testing for asthma is cost-saving and noninferior in improving health.
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    Genome-Wide Association Analysis in Asthma Subjects Identifies SPATS2L as a Novel Bronchodilator Response Gene
    (Public Library of Science, 2012) Himes, Blanca; Jiang, Xiaofeng; Hu, Ruoxi; Wu, Ann; Lasky-Su, Jessica; Klanderman, Barbara J.; Ziniti, John; Senter-Sylvia, Jody; Lima, John J.; Irvin, Charles G.; Peters, Stephen P.; Meyers, Deborah A.; Bleecker, Eugene R.; Kubo, Michiaki; Tamari, Mayumi; Nakamura, Yusuke; Szefler, Stanley J.; Lemanske, Robert F.; Zeiger, Robert S.; Strunk, Robert C.; Martinez, Fernando D.; Hanrahan, John P.; Koppelman, Gerard H.; Postma, Dirkje S.; Nieuwenhuis, Maartje A. E.; Vonk, Judith M.; Panettieri, Reynold A.; Markezich, Amy; Israel, Elliot; Carey, Vincent; Tantisira, Kelan; Litonjua, Augusto A.; Lu, Quan; Weiss, Scott
    Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS.
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    Asthma Self-assessment in a Medicaid Population
    (BioMed Central, 2009) Wu, Ann; Glauber, James Howard; Gay, Charlene; Lieu, Tracy
    Background: Self-assessment of symptoms by patients with chronic conditions is an important element of disease management. A recent study in a commercially-insured population found that patients who received automated telephone calls for asthma self-assessment felt they benefitted from the calls. Few studies have evaluated the effectiveness of disease self-assessment in Medicaid populations. The goals of this study were to: (1) assess the feasibility of asthma self-assessment in a population predominantly insured by Medicaid, (2) study whether adding a gift card incentive increased completion of the self-assessment survey, and (3) evaluate how the self-assessment affected processes and outcomes of care. Methods: We studied adults and children aged 4 years and older who were insured by a Medicaid-focused managed care organization (MCO) in a pre- and post-intervention study. During the pre-incentive period, patients with computerized utilization data that met specific criteria for problematic asthma control were mailed the Asthma Control Test (ACT), a self-assessment survey, and asked to return it to the MCO. During the intervention period, patients were offered a $20 gift card for returning the completed ACT to the MCO. To evaluate clinical outcomes, we used computerized claims data to assess the number of hospitalization visits and emergency department visits experienced in the 3 months after receiving the ACT. To evaluate whether the self-management intervention improved processes of care, we conducted telephone interviews with patients who returned or did not return the ACT by mail. Results: During the pre-incentive period, 1183 patients were identified as having problems with asthma control; 25 (2.0%) of these returned the ACT to the MCO. In contrast, during the incentive period, 1612 patients were identified as having problems with asthma control and 87 (5.4%) of these returned the ACT to the MCO (p < 0.0001). Of all 95 ACTs that were returned, 87% had a score of 19 or less, which suggested poor asthma control. During the 3 months after they received the ACT, patients who completed it had similar numbers of outpatient visits, emergency department visits, and hospitalizations for asthma as patients who did not complete the ACT. We completed interviews with 95 patients, including 28 who had completed the ACT and 67 who had not. Based on an ACT administered at the time of the interview, patients who had previously returned the ACT to the MCO had asthma control similar to those who had not (mean scores of 14.2 vs. 14.6, p = 0.70). Patients had similar rates of contacting their providers within the past 2 months whether they had completed the mailed ACT or not (71% vs. 76%, p = 0.57). Conclusion: Mailing asthma self-assessment surveys to patients with poorly controlled asthma was not associated with better asthma-associated outcomes or processes of care in the Medicaid population studied. Adding a gift card incentive did not meaningfully increase response rates. Asthma disease management programs for Medicaid populations will most likely need to involve alternative strategies for engaging patients and their providers in managing their conditions.
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    Asthma-susceptibility variants identified using probands in case-control and family-based analyses
    (BioMed Central, 2010) Murphy, Amy J; Soto-Quiros, Manuel E; Avila, Lydiana; Celedón, Juan C; O'Connor, George T; Himes, Blanca; Lasky-Su, Jessica; Wu, Ann; Wilk, Jemma; Hunninghake, Gary; Klanderman, Barbara; Lazarus, Ross; Lange, Christoph; Raby, Benjamin; Silverman, Edwin; Weiss, Scott
    Background: Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs. Methods: We used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings. Results: We found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung. Conclusions: Our results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.