199 results on '"Larkin, Emma"'
Search Results
152. Not out of Hate.
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Larkin, Emma
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MYANMAR politics & government ,NONFICTION - Abstract
The article reviews the book "Not Out of Hate," by Ma Ma Lay.
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- 2008
153. Book Reviews.
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Davren, Moira, Larkin, Emma, and McSherry, Dominic
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- MENTAL Health Services for Minority Ethnic Children & Adolescents (Book), SAFE Place for Caleb: An Interactive Book for Kids, Teens & Adults With Issues of Attachment, Grief & Loss or Early Trauma, A (Book), LEARN the Child: Helping Looked After Children to Learn: A Good Practice for Social Workers, Carers & Teachers (Book), MALEK, Mhemooda, JOUGHIN, Carol, CHARA, Kathleen A., CHARA, Paul J., CAIRNS, Kate, STANWAY, Chris
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Reviews several books related to child care and teachers. "Mental Health Services for Minority Ethnic Children and Adolescents," edited by Mhemooda Malek and Carol Joughin; "A Safe Place for Caleb: An Interactive Book for Kids, Teens & Adults with Issues of Attachment, Grief & Loss, or Early Trauma," by Kathleen A. Chara and Paul J. Chara, Jr.; "Learn the Child: Helping Looked After Children to Learn: A Good Practice Guide for Social Workers, Carers & Teachers," by Kate Cairns and Chris Stanway.
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- 2005
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154. A Genetic Analysis of Correlated Traits: The Apnea Hypopnea Index and Body Mass Index
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Larkin, Emma Katherine
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- Statistics, sleep apnea, body mass index, linkage analysis, genetic epidemiology
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In order to understand the genetics of sleep apnea, it is important to dissect the relationship between two highly correlated traits: the apnea hypopnea index (AHI), its main metric, and body mass index (BMI), a strong risk factor for sleep apnea. Genotyping data from 2 separate 10 cM genome scans of the Cleveland Family Study of Sleep Apnea were pooled to yield a data set with 634 individuals from 128 African American families and 641 individuals from 109 European Americans families. Heritability and segregation analyses were performed for a variety of AHI measurements which identified the lowest AHI measurement from longitudinal data as the optimal phenotype for linkage analysis. Univariate linkage analyses, using Haseman-Elston regression of sibling pairs and pedigree based variance component linkage analyses, were performed to identify areas where there are potential underlying quantitative trait loci for AHI that are independent of BMI and/or loci that are acting pleiotropically on both AHI and BMI together. A simulation study was proposed to assess the significance of differences in linkage peaks for two correlated traits at the same chromosomal location. Additional bivariate modeling and interaction modeling helped tease apart the relationship between the AHI and BMI. In European Americans, the most promising area of linkage to AHI was located near the orexin 2 receptor on chromosome 6, where there was evidence for underlying disease susceptibility loci for AHI that operate independently of BMI and act pleiotropically on BMI. Additional gene by BMI modeling increased the evidence for linkage to AHI on chromosomes 6, 10 and 19 in European Americans. In African Americans, the most suggestive area of linkage to a locus unique to AHI was on chromosome 8p11.1-11.2. There was also evidence in African Americans for a putative quantitative trait locus, acting on both BMI and AHI, near the serotonin 2A receptor on chromosome 13.
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- 2007
155. A Whole-Genome Scan for Obstructive Sleep Apnea and Obesity.
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Palmer, Lyle J., Buxbaum, Sarah G., Larkin, Emma, Patel, Sanjay R., Elston, Robert C., Tishler, Peter V., and Redline, Susan
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SLEEP apnea syndromes , *DISEASE susceptibility - Abstract
Obstructive sleep apnea (OSA) is a common, chronic, complex disease associated with serious cardiovascular and neuropsychological sequelae and with substantial social and economic costs. Along with male gender, obesity is the most characteristic feature of OSA in adults. To identify susceptibility loci for OSA, we undertook a 9-cM genome scan in 66 white pedigrees (n = 349 subjects) ascertained on the basis of either an affected individual with laboratory-confirmed OSA or a proband who was a neighborhood control individual. Multipoint variance-component linkage analysis was performed for the OSA-associated quantitative phenotypes apnea-hypopnea index (AHI) and body mass index (BMI). Candidate regions on chromosomes 1p (LOD score 1.39), 2p (LOD score 1.64), 12p (LOD score 1.43), and 19p (LOD score 1.40) gave the most evidence for linkage to AHI. BMI was also linked to multiple regions, most significantly to markers on chromosomes 2p (LOD score 3.08), 7p (LOD score 2.53), and 12p (LOD score 3.41). Extended modeling indicated that the evidence for linkage to AHI was effectively removed after adjustment for BMI, with the exception of the candidate regions on chromosomes 2p (adjusted LOD score 1.33) and 19p (adjusted LOD score 1.45). After adjustment for AHI, the primary linkages to BMI remained suggestive but were roughly halved. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity and that the interrelationship of OSA and obesity in white individuals may be partially explained by a common causal pathway involving one or more genes regulating both AHI and BMI levels. [ABSTRACT FROM AUTHOR]
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- 2003
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156. Trust and Trauma.
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LARKIN, EMMA
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FICTION , *TWENTIETH century ,HISTORY of Myanmar - Abstract
The article reviews the book "Miss Burma," by Charmaine Craig.
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- 2017
157. A Respiratory Syncytial Virus Attachment Gene Variant Associated with More Severe Disease in Infants Decreases Fusion Protein Expression, Which May Facilitate Immune Evasion.
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Human, Stacey, Hotard, Anne L., Rostad, Christina A., Sujin Lee, McCormick, Louise, Larkin, Emma K., Peret, Teresa C. T., Jorba, Jaume, Lanzone, Joseph, Gebretsadik, Tebeb, Williams, John V., Bloodworth, Melissa, Stier, Matthew, Carroll, Kecia, Peebles Jr., R. Stokes, Anderson, Larry J., Hartert, Tina V., and Moore, Martin L.
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RESPIRATORY syncytial virus , *CHIMERIC proteins , *GENETIC mutation , *PROTEIN expression , *INFANT diseases - Abstract
This study identified a genotype of respiratory syncytial virus (RSV) associated with increased acute respiratory disease severity in a cohort of previously healthy term infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4th position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wildtype A2 strain G gene (one stop codon preceding a wild-type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulenceassociated combination were generated and characterized. Infection with the recombinant A4G (rA4G) RSV mutant resulted in transcriptional readthrough and lower G and fusion (F) protein levels than for the wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational readthrough. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naive BALB/c mice compared to that for wild-type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of preexisting immunity than rA4G RSV. Together, these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains. [ABSTRACT FROM AUTHOR]
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- 2021
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158. Orwell's Guide to Making Jam.
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Larkin, Emma
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MEMOIRS , *NONFICTION - Abstract
The article presents a review of the book "Diaries" by George Orwell.
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- 2012
159. The New Roads Of Mandalay.
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Larkin, Emma
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GEOPOLITICS , *NONFICTION - Abstract
The article reviews the book "Where China Meets India: Burma and the New Crossroads of Asia," by Thant Myint-U.
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- 2011
160. Interference Between Respiratory Syncytial Virus and Human Rhinovirus Infection in Infancy.
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Achten, Niek B., Pingsheng Wu, Bont, Louis, Blanken, Maarten O., Gebretsadik, Tebeb, Chappell, James D., Li Wang, Chang Yu, Larkin, Emma K., Carroll, Kecia N., Anderson, Larry J., Moore, Martin L., Sloan, Chantel D., Hartert, Tina V., Wu, Pingsheng, Wang, Li, and Yu, Chang
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RESPIRATORY syncytial virus infections , *COMMON cold in infants , *VIRUS interference , *RESPIRATORY infections , *POLYMERASE chain reaction - Abstract
Background: Respiratory syncytial virus (RSV) and human rhinovirus (HRV) are the most common viruses associated with acute respiratory tract infections in infancy. Viral interference is important in understanding respiratory viral circulation and the impact of vaccines.Methods: To study viral interference, we evaluated cases of RSV and HRV codetection by polymerase chain reaction in 2 prospective birth cohort studies (the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure [INSPIRE] study and the Tennessee Children's Respiratory Initiative [TCRI]) and a double-blinded, randomized, controlled trial (MAKI), using adjusted multivariable regression analyses.Results: Among 3263 respiratory tract samples, 24.5% (798) and 37.3% (1216) were RSV and HRV positive, respectively. The odds of HRV infection were significantly lower in RSV-infected infants in all cohorts, with adjusted odds ratios of 0.30 (95% confidence interval [CI], .22-.40 in the INSPIRE study, 0.18 (95% CI, .11-.28) in the TCRI (adjusted for disease severity), and 0.34 (95% CI, .16-.72) in the MAKI trial. HRV infection was significantly more common among infants administered RSV immunoprophylaxis, compared with infants who did not receive immunoprophylaxis (OR, 1.65; 95% CI, 1.65-2.39).Conclusions: A negative association of RSV on HRV codetection was consistently observed across populations, seasons, disease severity, and geographical regions. Suppressing RSV infection by RSV immunoprophylaxis might increase the risk of having HRV infection. [ABSTRACT FROM AUTHOR]- Published
- 2017
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161. Differences in the Nasopharyngeal Microbiome During Acute Respiratory Tract Infection With Human Rhinovirus and Respiratory Syncytial Virus in Infancy.
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Rosas-Salazar, Christian, Shilts3,4,6, Meghan H., Tovchigrechko, Andrey, Schobel, Seth, Chappell, James D., Larkin, Emma K., Shankar, Jyoti, Yooseph, Shibu, Nelson, Karen E., Halpin, Rebecca A., Moore, Martin L., Anderson, Larry J., Stokes Peebles Jr, R., Das, Suman R., Hartert, Tina V., Shilts, Meghan H, and Peebles, R Stokes Jr
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HUMAN microbiota , *COMMON cold treatments , *POLYMERASE chain reaction , *MOLECULAR structure of ribosomal RNA , *BACTERIA classification , *NASOPHARYNX microbiology , *BACTERIA , *COMPARATIVE studies , *DNA , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *PICORNAVIRUS infections , *RESEARCH , *RESPIRATORY infections , *RNA , *EVALUATION research , *RESPIRATORY syncytial virus infections , *SEQUENCE analysis , *DISEASE complications ,RESPIRATORY infection treatment - Abstract
Respiratory viruses alter the nasopharyngeal microbiome and may be associated with a distinct microbial signature. To test this hypothesis, we compared the nasopharyngeal microbiome of 135 previously healthy infants with acute respiratory infection due to human rhinovirus (HRV; n = 52) or respiratory syncytial virus (RSV; n = 83). The nasopharyngeal microbiome was assessed by sequencing the V4 region of the 16S ribosomal RNA. Respiratory viruses were identified by quantitative reverse-transcription polymerase chain reaction. We found significant differences in the overall taxonomic composition and abundance of certain bacterial genera between infants infected with HRV and those infected with RSV. Our results suggest that respiratory tract viral infections are associated with different nasopharyngeal microbial profiles. [ABSTRACT FROM AUTHOR]
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- 2016
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162. Minimally Invasive Sampling Method Identifies Differences in Taxonomic Richness of Nasal Microbiomes in Young Infants Associated with Mode of Delivery.
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Shilts, Meghan, Rosas-Salazar, Christian, Tovchigrechko, Andrey, Larkin, Emma, Torralba, Manolito, Akopov, Asmik, Halpin, Rebecca, Peebles, R., Moore, Martin, Anderson, Larry, Nelson, Karen, Hartert, Tina, and Das, Suman
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HUMAN microbiota , *RIBOSOMAL RNA , *RESPIRATORY infections , *WHEEZE , *NUCLEOTIDE sequencing , *INFANT health - Abstract
To date, there is a limited understanding of the role of the airway microbiome in the early life development of respiratory diseases such as asthma, partly due to a lack of simple and minimally invasive sample collection methods. In order to characterize the baseline microbiome of the upper respiratory tract (URT) in infants, a comparatively non-invasive method for sampling the URT microbiome suitable for use in infants was developed. Microbiome samples were collected by placing filter paper in the nostrils of 33 healthy, term infants enrolled as part of the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure (INSPIRE) study. After bacterial genomic DNA was extracted from the filters, amplicons were generated with universal primers targeting the V1-V3 region of the 16S rRNA gene. This method was capable of capturing a wide variety of taxa expected to inhabit the nasal cavity. Analyses stratifying subjects by demographic and environmental factors previously observed or predicted to influence microbial communities were performed. Microbial community richness was found to be higher in infants who had been delivered via Cesarean section and in those who had been formula-fed; an association was observed between diet and delivery, which confounds this analysis. We have established a baseline URT microbiome using a non-invasive filter paper nasal sampling for this population, and future studies will be performed in this large observational cohort of infants to investigate the relationship between viral infections, the URT microbiota, and the development of childhood wheezing illnesses. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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163. Asthma Treatments and Mental Health Visits After a Food and Drug Administration Label Change for Leukotriene Inhibitors.
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Lu, Christine Y., Fang Zhang, Lakoma, Matthew D., Butler, Melissa G., Fung, Vicki, Larkin, Emma K., Kharbanda, Elyse O., Vollmer, William M., Lieu, Tracy, Soumerai, Stephen B., and Ann Chen Wu
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ASTHMA prevention , *ACADEMIC medical centers , *CONFIDENCE intervals , *MENTAL depression , *DRUG labeling , *MENTAL health , *REGRESSION analysis , *RESEARCH funding , *SUICIDAL ideation , *DATA analysis software , *MONTELUKAST , *LEUKOTRIENE antagonists - Abstract
Purpose: In 2009, the US Food and Drug Administration (FDA) mandated a label change for leukotriene inhibitors (LTIs) to include neuropsychiatric adverse events (eg, depression and suicidality) as a precaution. This study investigated how this label change affected the use of LTIs and other asthma controller medications, mental health visits, and suicide attempts. Methods: We analyzed data (2005-2010) from 5 large health plans in the US Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network. The study cohort included children and adolescents (n = 30,000), young adults (n = 20,0), and adults (n = 90,000) with asthma. We used interrupted time series to examine changes in rates of LTI dispensings, non-LTI dispensings, mental health visits, and suicide attempts (using a validated algorithm based on a combination of diagnoses of injury or poisoning and psychiatric conditions). Findings: The label change was associated with abrupt reductions in LTI use among all age groups (relative reductions of 8.3%, 15.1%, and 6.0% among adolescents, young adults, and adults, respectively, compared with expected rates at 1 year after the warnings). Although we detected immediate offset increases in non-LTI asthma medication use, these increases were not sustained among adolescents and young adults. There were small increases in mental health visits among LTI users. Implications: The FDA label change for LTIs communicated possible risk of neuropsychiatric events. Communication and enhanced awareness may have increased reporting of mental health symptoms among young adults and adults. It is important to assess intended and unintended consequences of FDA warnings and label changes. [ABSTRACT FROM AUTHOR]
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- 2015
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164. Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans.
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Ellis, Jaclyn, Lange, Ethan, Li, Jin, Dupuis, Josee, Baumert, Jens, Walston, Jeremy, Keating, Brendan, Durda, Peter, Fox, Ervin, Palmer, Cameron, Meng, Yan, Young, Taylor, Farlow, Deborah, Schnabel, Renate, Marzi, Carola, Larkin, Emma, Martin, Lisa, Bis, Joshua, Auer, Paul, and Ramachandran, Vasan
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C-reactive protein , *CARDIOVASCULAR diseases , *MEDICAL genetics , *ACUTE phase proteins , *GENETICS of race - Abstract
C-reactive protein (CRP) is a heritable biomarker of systemic inflammation and a predictor of cardiovascular disease (CVD). Large-scale genetic association studies for CRP have largely focused on individuals of European descent. We sought to uncover novel genetic variants for CRP in a multiethnic sample using the ITMAT Broad-CARe (IBC) array, a custom 50,000 SNP gene-centric array having dense coverage of over 2,000 candidate CVD genes. We performed analyses on 7,570 African Americans (AA) from the Candidate gene Association Resource (CARe) study and race-combined meta-analyses that included 29,939 additional individuals of European descent from CARe, the Women's Health Initiative (WHI) and KORA studies. We observed array-wide significance ( p < 2.2 × 10) for four loci in AA, three of which have been reported previously in individuals of European descent ( IL6R, p = 2.0 × 10; CRP, p = 4.2 × 10; APOE, p = 1.6 × 10). The fourth significant locus, CD36 ( p = 1.6 × 10), was observed at a functional variant (rs3211938) that is extremely rare in individuals of European descent. We replicated the CD36 finding ( p = 1.8 × 10) in an independent sample of 8,041 AA women from WHI; a meta-analysis combining the CARe and WHI AA results at rs3211938 reached genome-wide significance ( p = 1.5 × 10). In the race-combined meta-analyses, 13 loci reached significance, including ten ( CRP, TOMM40/APOE/APOC1, HNF1A, LEPR, GCKR, IL6R, IL1RN, NLRP3, HNF4A and BAZ1B/BCL7B) previously associated with CRP, and one ( ARNTL) previously reported to be nominally associated with CRP. Two novel loci were also detected ( RPS6KB1, p = 2.0 × 10; CD36, p = 1.4 × 10). These results highlight both shared and unique genetic risk factors for CRP in AA compared to populations of European descent. [ABSTRACT FROM AUTHOR]
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- 2014
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165. Enhanced Statistical Tests for GWAS in Admixed Populations: Assessment using African Americans from CARe and a Breast Cancer Consortium.
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Pasaniuc, Bogdan, Zaitlen, Noah, Lettre, Guillaume, Chen, Gary K., Tandon, Arti, Kao, W. H. Linda, Ruczinski, Ingo, Fornage, Myriam, Siscovick, David S., Xiaofeng Zhu, Larkin, Emma, Lange, Leslie A., Cupples, L. Adrienne, Qiong Yang, Akylbekova, Ermeg L., Musani, Solomon K., Divers, Jasmin, Mychaleckyj, Joe, Mingyao Li, and Papanicolaou, George J.
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AFRICAN Americans , *BREAST cancer , *CASE-control method , *GENEALOGY , *CHROMOSOMES , *GENE mapping , *GENETICS education - Published
- 2011
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166. Using urine metabolomics to understand the pathogenesis of infant respiratory syncytial virus (RSV) infection and its role in childhood wheezing.
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Turi, Kedir N., Romick-Rosendale, Lindsey, Gebretsadik, Tebeb, Watanabe, Miki, Brunwasser, Steven, Anderson, Larry J., Moore, Martin L., Larkin, Emma K., Peebles, Ray Stokes, and Hartert, Tina V.
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RESPIRATORY syncytial virus infections , *URINALYSIS , *WHEEZE , *CHILDREN'S health , *MULTIVARIATE analysis - Abstract
Background: Respiratory syncytial virus (RSV) infection in infants causes significant morbidity and is the strongest risk factor associated with asthma. Metabolites, which reflect the interactions between host cell and virus, provide an opportunity to identify the pathways that underlie severe infections and asthma development.Objective: To study metabolic profile differences between infants with RSV infection, and human rhinovirus (HRV) infection, and healthy infants. To compare infant metabolic differences between children who do and do not wheeze.Methods: In a term birth cohort, urine was collected while healthy and during acute viral respiratory infection with RSV and HRV. We used 1H-NMR to identify urinary metabolites. Multivariate and univariate statistics were used to discriminate metabolic profiles of infants with either RSV ARI, or HRV ARI, and healthy infants. Multivariable logistic regression was used to assess the association of urine metabolites with 1st-, 2nd-, and 3rd-year recurrent wheezing.Results: Several metabolites in nicotinate and nicotinamide metabolism pathways were down-regulated in infants with RSV infection compared to healthy controls. There were no significant differences in metabolite profiles between infants with RSV infection and infants with HRV Infection. Alanine was strongly associated with reduced risk of 1st-year wheezing (OR 0.18[0.0, 0.46]) and 2nd-year wheezing (OR 0.31[0.13, 0.73]), while 2-hydroxyisobutyric acid was associated with increased 3rd-year wheezing (OR 5.02[1.49, 16.93]) only among the RSV infected subset.Conclusion: The metabolites associated with infant RSV infection and recurrent-wheezing are indicative of viral takeover of the cellular machinery and resources to enhance virulence, replication, and subversion of the host immune-response, highlighting metabolic pathways important in the pathogenesis of RSV infection and wheeze development. [ABSTRACT FROM AUTHOR]
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- 2018
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167. Viral Genetic Determinants of Prolonged Respiratory Syncytial Virus Infection Among Infants in a Healthy Term Birth Cohort.
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Lawless D, McKennan CG, Das SR, Junier T, Xu ZM, Anderson LJ, Gebretsadik T, Shilts MH, Larkin E, Rosas-Salazar C, Chappell JD, Fellay J, and Hartert TV
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- Humans, Infant, Birth Cohort, Genome-Wide Association Study, Genetic Predisposition to Disease, Respiratory Syncytial Virus Infections epidemiology, Respiratory Syncytial Virus Infections genetics, Respiratory Syncytial Virus, Human genetics
- Abstract
Background: Respiratory syncytial virus (RSV) is associated with acute respiratory infection. We sought to identify RSV variants associated with prolonged infection., Methods: Among healthy term infants we identified those with prolonged RSV infection and conducted (1) a human genome-wide association study (GWAS) to test the dependence of infection risk on host genotype, (2) a viral GWAS for association with prolonged RSV infection using RSV whole-genome sequencing, (3) an analysis of all viral public sequences, (4) an assessment of immunological responses, and (5) a summary of all major functional data. Analyses were adjusted for viral/human population structure and host factors associated with infection risk., Results: We identified p.E123K/D and p.P218T/S/L in G protein that were associated with prolonged infection (Padj = .01). We found no evidence of host genetic risk for infection. The RSV variant positions approximate sequences that could bind a putative viral receptor, heparan sulfate., Conclusions: Using analysis of both viral and host genetics we identified a novel RSV variant associated with prolonged infection in otherwise healthy infants and no evidence supporting host genetic susceptibility to infection. As the capacity of RSV for chronicity and its viral reservoir are not defined, these findings are important for understanding the impact of RSV on chronic disease and endemicity., Competing Interests: Potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Funding for this work has been supplied by the NIH and the SNSF. Funding to pay the Open Access publication charges for this article was provided by NIH. Tina Hartert; consulting fees: Sanofi Pasteur scientific advisory board RSV vaccines, participation on a data safety monitoring board: Pfizer. Larry J. Anderson; Grants or contracts (exlcuding funding for this project): CDC contract for herpes simplex antibody testing, subcontract with Sciogen on an NIH SBIR for RSV vaccines, contract with Pfizer to serologic testing studies of RSV, consulting fees: Janssen scientific advisory board RSV vaccines, ADVI scientific advisory board RSV vaccines, and Bavarian Nordic scientific advisory board, patents planned, issued or pending: RSV vaccines and Immune treatment, and RSV VLP vaccines., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2023
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168. Corrigendum: A Mini-Review of Pharmacological and Psychosocial Interventions for Reducing Irritability Among Youth With ADHD.
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Breaux R, Dunn NC, Swanson CS, Larkin E, Waxmonsky J, and Baweja R
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[This corrects the article DOI: 10.3389/fpsyt.2022.794044.]., (Copyright © 2022 Breaux, Dunn, Swanson, Larkin, Waxmonsky and Baweja.)
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- 2022
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169. A Mini-Review of Pharmacological and Psychosocial Interventions for Reducing Irritability Among Youth With ADHD.
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Breaux R, Dunn NC, Swanson CS, Larkin E, Waxmonsky J, and Baweja R
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Approximately a third of children and adolescents with attention-deficit/hyperactivity disorder (ADHD) experience significant irritability; despite this, no study has reviewed whether interventions for youth with ADHD can improve irritability. This mini review sought to address this gap in the literature by discussing existing pharmacological and psychosocial interventions for irritability among children and adolescents with ADHD. A literature search was conducted in April 2021, with a total of 12 intervention articles identified (six pharmacological, one psychosocial, five combined). Studies were excluded if they did not involve an intervention, a measure of irritability, or the population was not youth with ADHD. Of these articles, two were with an ADHD only sample; seven included ADHD with comorbid disruptive behavior, disruptive mood dysregulation disorder (DMDD), or severe mood dysregulation (SMD); and three included ADHD with comorbid autism spectrum disorder (ASD). Findings suggest that central nervous system stimulants used alone or in combination with behavior therapy are effective at reducing irritability in youth with ADHD only or comorbid ADHD and DMDD/SMD. Less evidence was found for the efficacy of guanfacine and atomoxetine for youth with ADHD only or comorbid ADHD and ASD. Parent training alone or in combination with atomoxetine was found to be effective at reducing irritability in youth with comorbid ADHD and ASD. Future research assessing the efficacy of other psychosocial interventions, particularly cognitive behavioral therapy is necessary, as are randomized trials assessing intervention sequencing and intensity among youth with ADHD. Researchers are advised to utilize well-validated measures of irritability in future research., Competing Interests: In the past three years, JW has received research funding from Supernus and served as a consultant for Adlon Therapeutics and Intracellular Therapies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Breaux, Dunn, Swanson, Larkin, Waxmonsky and Baweja.)
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- 2022
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170. A Respiratory Syncytial Virus Attachment Gene Variant Associated with More Severe Disease in Infants Decreases Fusion Protein Expression, Which May Facilitate Immune Evasion.
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Human S, Hotard AL, Rostad CA, Lee S, McCormick L, Larkin EK, Peret TCT, Jorba J, Lanzone J, Gebretsadik T, Williams JV, Bloodworth M, Stier M, Carroll K, Peebles RS Jr.,, Anderson LJ, Hartert TV, and Moore ML
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- Animals, Cell Line, Gene Expression Regulation, Viral, Genotype, Humans, Infant, Mice, Mice, Inbred BALB C, Mutation, Phylogeny, Respiratory Syncytial Virus Infections immunology, Respiratory Syncytial Virus Infections pathology, Respiratory Syncytial Virus, Human classification, Respiratory Syncytial Virus, Human genetics, Respiratory Syncytial Virus, Human isolation & purification, Severity of Illness Index, Viral Fusion Proteins immunology, Viral Load genetics, Virulence genetics, Virus Replication genetics, Immune Evasion genetics, Respiratory Syncytial Virus Infections virology, Respiratory Syncytial Virus, Human pathogenicity, Viral Fusion Proteins genetics
- Abstract
This study identified a genotype of respiratory syncytial virus (RSV) associated with increased acute respiratory disease severity in a cohort of previously healthy term infants. The genotype (2stop+A4G) consists of two components. The A4G component is a prevalent point mutation in the 4th position of the gene end transcription termination signal of the G gene of currently circulating RSV strains. The 2stop component is two tandem stop codons at the G gene terminus, preceding the gene end transcription termination signal. To investigate the biological role of these RSV G gene mutations, recombinant RSV strains harboring either a wild-type A2 strain G gene (one stop codon preceding a wild-type gene end signal), an A4G gene end signal preceded by one stop codon, or the 2stop+A4G virulence-associated combination were generated and characterized. Infection with the recombinant A4G (rA4G) RSV mutant resulted in transcriptional readthrough and lower G and fusion (F) protein levels than for the wild type. Addition of a second stop codon preceding the A4G point mutation (2stop+A4G) restored G protein expression but retained lower F protein levels. These data suggest that RSV G and F glycoprotein expression is regulated by transcriptional and translational readthrough. Notably, while rA4G and r2stop+A4G RSV were attenuated in cells and in naive BALB/c mice compared to that for wild-type RSV, the r2stop+A4G RSV was better able to infect BALB/c mice in the presence of preexisting immunity than rA4G RSV. Together, these factors may contribute to the maintenance and virulence of the 2stop+A4G genotype in currently circulating RSV-A strains. IMPORTANCE Strain-specific differences in respiratory syncytial virus (RSV) isolates are associated with differential pathogenesis in mice. However, the role of RSV genotypes in human infection is incompletely understood. This work demonstrates that one such genotype, 2stop+A4G, present in the RSV attachment (G) gene terminus is associated with greater infant disease severity. The genotype consists of two tandem stop codons preceding an A-to-G point mutation in the 4th position of the G gene end transcription termination signal. Virologically, the 2stop+A4G RSV genotype results in reduced levels of the RSV fusion (F) glycoprotein. A recombinant 2stop+A4G RSV was better able to establish infection in the presence of existing RSV immunity than a virus harboring the common A4G mutation. These data suggest that regulation of G and F expression has implications for virulence and, potentially, immune evasion., (Copyright © 2020 American Society for Microbiology.)
- Published
- 2020
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171. Association of newborn screening metabolites with risk of wheezing in childhood.
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Donovan BM, Ryckman KK, Breheny PJ, Gebretsadik T, Turi KN, Larkin EK, Li Y, Dorley MC, and Hartert TV
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- Asthma etiology, Asthma physiopathology, Biomarkers blood, Child, Preschool, Dried Blood Spot Testing, Female, Humans, Infant, Infant, Newborn, Male, Prospective Studies, Risk Factors, Asthma blood, Neonatal Screening, Respiratory Sounds
- Abstract
Background: There are critical gaps in our understanding of the temporal relationships between metabolites and subsequent asthma development. This is the first study to examine metabolites from newborn screening in the etiology of early childhood wheezing., Methods: One thousand nine hundred and fifty one infants enrolled between 2012 and 2014 from pediatric practices located in Middle Tennessee in the population-based birth cohort study, the Infant Susceptibility to Pulmonary Infections and Asthma Following RSV Exposure Study (INSPIRE), were linked with metabolite data from the Tennessee Newborn Screening Program. The association between the levels of 37 metabolites and the number of wheezing episodes in the past 12 months was assessed at 1, 2, and 3 years of life., Results: Several metabolites were significantly associated with the number of wheezing episodes. Two acylcarnitines, C10:1 and C18:2, showed robust associations. Increasing levels of C10:1 were associated with increasing number of wheezing episodes at 2 years (OR 2.11, 95% CI 1.41-3.17) and 3 years (OR 2.56, 95% CI 1.59-4.11), while increasing levels of C18:2 were associated with increasing number of wheezing episodes at 1 year (OR 1.38, 95% CI 1.12-1.71) and 2 years (OR 1.47, 95% CI 1.17-1.84)., Conclusions: Identification of specific metabolites and associated pathways involved in wheezing pathogenesis offer insights into potential targets to prevent childhood asthma morbidity.
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- 2018
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172. Multiethnic Meta-Analysis Identifies RAI1 as a Possible Obstructive Sleep Apnea-related Quantitative Trait Locus in Men.
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Chen H, Cade BE, Gleason KJ, Bjonnes AC, Stilp AM, Sofer T, Conomos MP, Ancoli-Israel S, Arens R, Azarbarzin A, Bell GI, Below JE, Chun S, Evans DS, Ewert R, Frazier-Wood AC, Gharib SA, Haba-Rubio J, Hagen EW, Heinzer R, Hillman DR, Johnson WC, Kutalik Z, Lane JM, Larkin EK, Lee SK, Liang J, Loredo JS, Mukherjee S, Palmer LJ, Papanicolaou GJ, Penzel T, Peppard PE, Post WS, Ramos AR, Rice K, Rotter JI, Sands SA, Shah NA, Shin C, Stone KL, Stubbe B, Sul JH, Tafti M, Taylor KD, Teumer A, Thornton TA, Tranah GJ, Wang C, Wang H, Warby SC, Wellman DA, Zee PC, Hanis CL, Laurie CC, Gottlieb DJ, Patel SR, Zhu X, Sunyaev SR, Saxena R, Lin X, and Redline S
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Phosphatidylethanolamine N-Methyltransferase genetics, Sex Characteristics, Sterol Regulatory Element Binding Protein 1 genetics, Trans-Activators, ras Proteins genetics, Genome-Wide Association Study, Quantitative Trait Loci genetics, Sleep Apnea, Obstructive genetics, Sleep, REM physiology, Transcription Factors genetics
- Abstract
Obstructive sleep apnea (OSA) is a common heritable disorder displaying marked sexual dimorphism in disease prevalence and progression. Previous genetic association studies have identified a few genetic loci associated with OSA and related quantitative traits, but they have only focused on single ethnic groups, and a large proportion of the heritability remains unexplained. The apnea-hypopnea index (AHI) is a commonly used quantitative measure characterizing OSA severity. Because OSA differs by sex, and the pathophysiology of obstructive events differ in rapid eye movement (REM) and non-REM (NREM) sleep, we hypothesized that additional genetic association signals would be identified by analyzing the NREM/REM-specific AHI and by conducting sex-specific analyses in multiethnic samples. We performed genome-wide association tests for up to 19,733 participants of African, Asian, European, and Hispanic/Latino American ancestry in 7 studies. We identified rs12936587 on chromosome 17 as a possible quantitative trait locus for NREM AHI in men (N = 6,737; P = 1.7 × 10
-8 ) but not in women (P = 0.77). The association with NREM AHI was replicated in a physiological research study (N = 67; P = 0.047). This locus overlapping the RAI1 gene and encompassing genes PEMT1, SREBF1, and RASD1 was previously reported to be associated with coronary artery disease, lipid metabolism, and implicated in Potocki-Lupski syndrome and Smith-Magenis syndrome, which are characterized by abnormal sleep phenotypes. We also identified gene-by-sex interactions in suggestive association regions, suggesting that genetic variants for AHI appear to vary by sex, consistent with the clinical observations of strong sexual dimorphism.- Published
- 2018
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173. Variants in angiopoietin-2 (ANGPT2) contribute to variation in nocturnal oxyhaemoglobin saturation level.
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Wang H, Cade BE, Chen H, Gleason KJ, Saxena R, Feng T, Larkin EK, Vasan RS, Lin H, Patel SR, Tracy RP, Liu Y, Gottlieb DJ, Below JE, Hanis CL, Petty LE, Sunyaev SR, Frazier-Wood AC, Rotter JI, Post W, Lin X, Redline S, and Zhu X
- Subjects
- Adult, Female, Genetic Association Studies, Genetic Linkage, Genetic Predisposition to Disease, Haplotypes genetics, Humans, Male, Oxygen metabolism, Polymorphism, Single Nucleotide, Respiration genetics, Sleep genetics, Sleep Apnea Syndromes metabolism, Sleep Apnea Syndromes pathology, Angiopoietin-2 genetics, Oxygen Consumption genetics, Oxyhemoglobins genetics, Sleep Apnea Syndromes genetics
- Abstract
Genetic determinants of sleep-disordered breathing (SDB), a common set of disorders that contribute to significant cardiovascular and neuropsychiatric morbidity, are not clear. Overnight nocturnal oxygen saturation (SaO2) is a clinically relevant and easily measured indicator of SDB severity but its genetic contribution has never been studied. Our recent study suggests nocturnal SaO2 is heritable. We performed linkage analysis, association analysis and haplotype analysis of average nocturnal oxyhaemoglobin saturation in participants in the Cleveland Family Study (CFS), followed by gene-based association and additional tests in four independent samples. Linkage analysis identified a peak (LOD = 4.29) on chromosome 8p23. Follow-up association analysis identified two haplotypes in angiopoietin-2 (ANGPT2) that significantly contributed to the variation of SaO2 (P = 8 × 10-5) and accounted for a portion of the linkage evidence. Gene-based association analysis replicated the association of ANGPT2 and nocturnal SaO2. A rare missense SNP rs200291021 in ANGPT2 was associated with serum angiopoietin-2 level (P = 1.29 × 10-4), which was associated with SaO2 (P = 0.002). Our study provides the first evidence for the association of ANGPT2, a gene previously implicated in acute lung injury syndromes, with nocturnal SaO2, suggesting that this gene has a broad range of effects on gas exchange, including influencing oxygenation during sleep., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2016
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174. Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans.
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Cade BE, Chen H, Stilp AM, Gleason KJ, Sofer T, Ancoli-Israel S, Arens R, Bell GI, Below JE, Bjonnes AC, Chun S, Conomos MP, Evans DS, Johnson WC, Frazier-Wood AC, Lane JM, Larkin EK, Loredo JS, Post WS, Ramos AR, Rice K, Rotter JI, Shah NA, Stone KL, Taylor KD, Thornton TA, Tranah GJ, Wang C, Zee PC, Hanis CL, Sunyaev SR, Patel SR, Laurie CC, Zhu X, Saxena R, Lin X, and Redline S
- Abstract
Rationale: Obstructive sleep apnea is a common disorder associated with increased risk for cardiovascular disease, diabetes, and premature mortality. Although there is strong clinical and epidemiologic evidence supporting the importance of genetic factors in influencing obstructive sleep apnea, its genetic basis is still largely unknown. Prior genetic studies focused on traits defined using the apnea-hypopnea index, which contains limited information on potentially important genetically determined physiologic factors, such as propensity for hypoxemia and respiratory arousability., Objectives: To define novel obstructive sleep apnea genetic risk loci for obstructive sleep apnea, we conducted genome-wide association studies of quantitative traits in Hispanic/Latino Americans from three cohorts., Methods: Genome-wide data from as many as 12,558 participants in the Hispanic Community Health Study/Study of Latinos, Multi-Ethnic Study of Atherosclerosis, and Starr County Health Studies population-based cohorts were metaanalyzed for association with the apnea-hypopnea index, average oxygen saturation during sleep, and average respiratory event duration., Measurements and Main Results: Two novel loci were identified at genome-level significance (rs11691765, GPR83, P = 1.90 × 10
-8 for the apnea-hypopnea index, and rs35424364; C6ORF183/CCDC162P, P = 4.88 × 10-8 for respiratory event duration) and seven additional loci were identified with suggestive significance (P < 5 × 10-7 ). Secondary sex-stratified analyses also identified one significant and several suggestive associations. Multiple loci overlapped genes with biologic plausibility., Conclusions: These are the first genome-level significant findings reported for obstructive sleep apnea-related physiologic traits in any population. These findings identify novel associations in inflammatory, hypoxia signaling, and sleep pathways.- Published
- 2016
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175. Mismatching Among Guidelines, Providers, and Parents on Controller Medication Use in Children with Asthma.
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Wu AC, Li L, Fung V, Kharbanda EO, Larkin EK, Butler MG, Galbraith A, Miroshnik I, Davis RL, Horan K, and Lieu TA
- Subjects
- Adrenal Cortex Hormones therapeutic use, Adrenergic beta-Agonists therapeutic use, Child, Child, Preschool, Female, Health Personnel, Humans, Leukotriene Antagonists therapeutic use, Male, Surveys and Questionnaires, Anti-Asthmatic Agents therapeutic use, Asthma drug therapy, Parents, Practice Guidelines as Topic, Practice Patterns, Physicians'
- Abstract
Background: Underuse of controller medicines among children with asthma remains widespread despite national guidelines., Objectives: To (1) assess provider prescribing patterns for asthma controller medications; (2) assess how frequently parents' reports of their child's asthma controller medicine use were mismatched with their provider's recommendations; and (3) evaluate parent attitudes and demographic characteristics associated with these mismatches., Methods: In this cross-sectional study, we conducted linked surveys of parents and providers of children with probable persistent asthma in a Medicaid program and 4 commercial health plans in 2011. Probable persistent asthma was defined as a diagnosis of asthma and 1 or more controller medication dispensing., Results: This study included 740 children (mean age, 8.6 years). Providers for 50% of the children reported prescribing controller medications for daily year-round use, 41% for daily use during active asthma months, and 9% for intermittent use for relief. Among parents, 72% knew which class of controller medication the provider prescribed and 49% knew the administration frequency and the medication class. Parents were less likely to report the same controller medication type as the provider, irrespective of dose and frequency, if they were Latino (odds ratio [OR], 0.23; CI, 0.057-0.90), had a household smoker (OR, 2.87; CI, 0.42-19.6), or believed the controller medicine was not helping (OR, 0.15; CI, 0.048-0.45)., Conclusions: Mismatches between parent reports and providers intentions regarding how the child was supposed to use inhaled steroids occurred for half of the children. Efforts should focus on ways to reduce mismatches between parent and provider intentions regarding controller medication use., Competing Interests: The authors have no conflicts of interest., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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176. Nasopharyngeal Microbiome in Respiratory Syncytial Virus Resembles Profile Associated with Increased Childhood Asthma Risk.
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Rosas-Salazar C, Shilts MH, Tovchigrechko A, Chappell JD, Larkin EK, Nelson KE, Moore ML, Anderson LJ, Das SR, and Hartert TV
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- Female, Humans, Infant, Male, Risk, Asthma microbiology, Microbiota, Nasopharynx microbiology, Respiratory Syncytial Virus Infections microbiology
- Published
- 2016
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177. Identifying genetically driven clinical phenotypes using linear mixed models.
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Mosley JD, Witte JS, Larkin EK, Bastarache L, Shaffer CM, Karnes JH, Stein CM, Phillips E, Hebbring SJ, Brilliant MH, Mayer J, Ye Z, Roden DM, and Denny JC
- Subjects
- Adult, Aged, Aged, 80 and over, Exome, Female, Genetic Variation, Genome-Wide Association Study, Genotype, HLA Antigens genetics, Humans, Male, Middle Aged, Models, Genetic, Phenotype, Polymorphism, Single Nucleotide, White People genetics, Disease genetics, Genetic Predisposition to Disease
- Abstract
We hypothesized that generalized linear mixed models (GLMMs), which estimate the additive genetic variance underlying phenotype variability, would facilitate rapid characterization of clinical phenotypes from an electronic health record. We evaluated 1,288 phenotypes in 29,349 subjects of European ancestry with single-nucleotide polymorphism (SNP) genotyping on the Illumina Exome Beadchip. We show that genetic liability estimates are primarily driven by SNPs identified by prior genome-wide association studies and SNPs within the human leukocyte antigen (HLA) region. We identify 44 (false discovery rate q<0.05) phenotypes associated with HLA SNP variation and show that hypothyroidism is genetically correlated with Type I diabetes (rG=0.31, s.e. 0.12, P=0.003). We also report novel SNP associations for hypothyroidism near HLA-DQA1/HLA-DQB1 at rs6906021 (combined odds ratio (OR)=1.2 (95% confidence interval (CI): 1.1-1.2), P=9.8 × 10(-11)) and for polymyalgia rheumatica near C6orf10 at rs6910071 (OR=1.5 (95% CI: 1.3-1.6), P=1.3 × 10(-10)). Phenome-wide application of GLMMs identifies phenotypes with important genetic drivers, and focusing on these phenotypes can identify novel genetic associations.
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- 2016
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178. A Phenome-Wide Association Study Identifies a Novel Asthma Risk Locus Near TERC.
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Claar DD, Larkin EK, Bastarache L, Blackwell TS, Loyd JE, Hartert TV, Denny JC, and Kropski JA
- Subjects
- Female, Genetic Association Studies, Genetic Loci, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, RNA physiology, Risk Factors, Telomerase physiology, Asthma genetics, Genetic Predisposition to Disease genetics, RNA genetics, Telomerase genetics
- Published
- 2016
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179. Common variants in DRD2 are associated with sleep duration: the CARe consortium.
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Cade BE, Gottlieb DJ, Lauderdale DS, Bennett DA, Buchman AS, Buxbaum SG, De Jager PL, Evans DS, Fülöp T, Gharib SA, Johnson WC, Kim H, Larkin EK, Lee SK, Lim AS, Punjabi NM, Shin C, Stone KL, Tranah GJ, Weng J, Yaffe K, Zee PC, Patel SR, Zhu X, Redline S, and Saxena R
- Subjects
- Cohort Studies, Ethnicity, Humans, Polymorphism, Single Nucleotide, Polysomnography, Time Factors, Receptors, Dopamine D2 genetics, Sleep genetics
- Abstract
Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2016
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180. Primary adherence to controller medications for asthma is poor.
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Wu AC, Butler MG, Li L, Fung V, Kharbanda EO, Larkin EK, Vollmer WM, Miroshnik I, Davis RL, Lieu TA, and Soumerai SB
- Subjects
- Administration, Inhalation, Adolescent, Adult, Black or African American statistics & numerical data, Aged, Child, Child, Preschool, Cohort Studies, Female, Hispanic or Latino statistics & numerical data, Humans, Infant, Infant, Newborn, Logistic Models, Male, Middle Aged, Multivariate Analysis, Retrospective Studies, Young Adult, Adrenal Cortex Hormones therapeutic use, Adrenergic beta-Agonists therapeutic use, Anti-Asthmatic Agents therapeutic use, Asthma drug therapy, Leukotriene Antagonists therapeutic use, Medication Adherence statistics & numerical data
- Abstract
Rationale: Few previous studies have evaluated primary adherence (whether a new prescription is filled within 30 d) to controller medications in individuals with persistent asthma., Objective: To compare adherence to the major controller medication regimens for asthma., Methods: This was a retrospective cohort study of enrollees from five large health plans. We used electronic medical data on patients of all ages with asthma who had experienced an asthma-related exacerbation in the prior 12 months. We studied adherence measures including proportion of days covered and primary adherence (first prescription filled within 30 d)., Measurements and Main Results: Our population included 69,652 subjects who had probable persistent asthma and were prescribed inhaled corticosteroids (ICSs), leukotriene antagonists (LTRAs), or ICS/long-acting β-agonists (ICS/LABAs). The mean age was 37 years and 58% were female. We found that 14-20% of subjects who were prescribed controller medicines for the first time did not fill their prescriptions. The mean proportion of days covered was 19% for ICS, 30% for LTRA, and 25% for ICS/LABA over 12 months. Using multivariate logistic regression, subjects prescribed LTRA were less likely to be primary adherent than subjects prescribed ICS (odds ratio, 0.82; 95% confidence interval, 0.74-0.92) or ICS/LABA (odds ratio, 0.88; 95% confidence interval, 0.80-0.97). Black and Latino patients were less likely to fill the prescription compared with white patients., Conclusions: Adherence to controller medications for asthma is poor. In this insured population, primary adherence to ICSs was better than to LTRAs and ICS/LABAs. Adherence as measured by proportion of days covered was better for LTRAs and ICS/LABAs than for ICSs.
- Published
- 2015
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181. New risk factors for adult-onset incident asthma. A nested case-control study of host antioxidant defense.
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Larkin EK, Gao YT, Gebretsadik T, Hartman TJ, Wu P, Wen W, Yang G, Bai C, Jin M, Roberts LJ 2nd, Gross M, Shu XO, and Hartert TV
- Subjects
- 1-Alkyl-2-acetylglycerophosphocholine Esterase physiology, Adult, Age of Onset, Aged, Asthma enzymology, Asthma immunology, Biomarkers blood, Biomarkers urine, Case-Control Studies, China, F2-Isoprostanes urine, Female, Humans, Micronutrients blood, Micronutrients immunology, Middle Aged, Platelet Activating Factor physiology, Prospective Studies, Protective Factors, Risk Factors, alpha-Tocopherol analysis, Antioxidants analysis, Asthma etiology, Oxidative Stress immunology, alpha-Tocopherol immunology
- Abstract
Rationale: Host antioxidant defense, consisting of enzymatic antioxidant activity and nonenzymatic antioxidant micronutrients, is implicated in asthma pathogenesis. Studies of antioxidant defense and adult incident asthma have either used measures of antioxidants estimated from questionnaires or not considered enzymatic aspects of host defense., Objectives: We conducted the first study designed and powered to investigate the association of antioxidant defenses on adult incident asthma., Methods: In a nested case-control study, we followed Shanghai women (aged 40-70 years) without prevalent asthma at baseline, over 8 years. Subjects with incident asthma were ascertained prospectively by gold standard testing of symptomatic women and matched to two asymptomatic control subjects., Measurements and Main Results: Baseline urinary F2-isoprostanes, plasma concentrations of antioxidant micronutrients (tocopherols, xanthines, carotenes, and lycopene), and antioxidant enzyme activity (platelet-activating factor acetylhydrolase [PAF-AH] and superoxide dismutase) were measured from samples collected before disease onset. Among 65,372 women, 150 (0.24%) developed asthma. F2-isoprostane levels before asthma onset were not different between cases and control subjects. Doubling of α-tocopherol concentrations and PAF-AH activity was associated with 50 and 37% decreased risk of incident asthma (α-tocopherol: adjusted odds ratio = 0.52; 95% confidence interval, 0.32-0.84; PAF-AH: adjusted odds ratio = 0.63; 95% confidence interval, 0.42-0.93)., Conclusions: In this prospective study, α-tocopherol, within normal reference ranges, and PAF-AH enzymatic activity were associated with decreased asthma development. These modifiable risk factors may be an effective strategy to test for primary asthma prevention.
- Published
- 2015
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182. Genome-wide scan of 29,141 African Americans finds no evidence of directional selection since admixture.
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Bhatia G, Tandon A, Patterson N, Aldrich MC, Ambrosone CB, Amos C, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Bock CH, Caporaso N, Casey G, Deming SL, Diver WR, Gapstur SM, Gillanders EM, Harris CC, Henderson BE, Ingles SA, Isaacs W, De Jager PL, John EM, Kittles RA, Larkin E, McNeill LH, Millikan RC, Murphy A, Neslund-Dudas C, Nyante S, Press MF, Rodriguez-Gil JL, Rybicki BA, Schwartz AG, Signorello LB, Spitz M, Strom SS, Tucker MA, Wiencke JK, Witte JS, Wu X, Yamamura Y, Zanetti KA, Zheng W, Ziegler RG, Chanock SJ, Haiman CA, Reich D, and Price AL
- Subjects
- Evolution, Molecular, Gene Frequency, Haplotypes, Humans, White People genetics, Black or African American, Black People genetics, Chromosomes, Human, Genetics, Population, Genome, Human genetics, Genome-Wide Association Study, Polymorphism, Single Nucleotide genetics, Selection, Genetic genetics
- Abstract
The extent of recent selection in admixed populations is currently an unresolved question. We scanned the genomes of 29,141 African Americans and failed to find any genome-wide-significant deviations in local ancestry, indicating no evidence of selection influencing ancestry after admixture. A recent analysis of data from 1,890 African Americans reported that there was evidence of selection in African Americans after their ancestors left Africa, both before and after admixture. Selection after admixture was reported on the basis of deviations in local ancestry, and selection before admixture was reported on the basis of allele-frequency differences between African Americans and African populations. The local-ancestry deviations reported by the previous study did not replicate in our very large sample, and we show that such deviations were expected purely by chance, given the number of hypotheses tested. We further show that the previous study's conclusion of selection in African Americans before admixture is also subject to doubt. This is because the FST statistics they used were inflated and because true signals of unusual allele-frequency differences between African Americans and African populations would be best explained by selection that occurred in Africa prior to migration to the Americas., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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183. Use of leukotriene receptor antagonists are associated with a similar risk of asthma exacerbations as inhaled corticosteroids.
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Wu AC, Li L, Fung V, Kharbanda EO, Larkin EK, Vollmer WM, Butler MG, Miroshnik I, Rusinak D, Davis RL, Hartert T, Weiss ST, and Lieu TA
- Subjects
- Administration, Inhalation, Adolescent, Asthma epidemiology, Child, Child, Preschool, Emergency Service, Hospital statistics & numerical data, Female, Hospitalization statistics & numerical data, Humans, Male, Retrospective Studies, Rhinitis, Allergic drug therapy, Rhinitis, Allergic epidemiology, Risk, Treatment Outcome, United States epidemiology, Adrenal Cortex Hormones therapeutic use, Adrenergic beta-Agonists therapeutic use, Anti-Asthmatic Agents therapeutic use, Asthma drug therapy, Leukotriene Antagonists therapeutic use
- Abstract
Background: Based on results of clinical trials, inhaled corticosteroids (ICS) are the most-effective controller medications for preventing asthma-related exacerbations, yet few studies in real-life populations have evaluated the comparative effectiveness of ICS., Objective: To determine the likelihood of asthma exacerbations among children with asthma after initiation of controller medications: ICS, leukotriene antagonists (LTRA), and ICS-long-acting β-agonist (LABA) combination therapy., Methods: This was a retrospective cohort study of subjects who were part of the Population-Based Effectiveness in Asthma and Lung Diseases Network. We conducted Cox regression analyses by adjusting for baseline covariates, adherence by using proportion of days covered, and high-dimensional propensity scores. The main outcome measurements were emergency department visits, hospitalizations, or oral corticosteroid use., Results: Our population included 15,567 health plan subjects and 10,624 TennCare Medicaid subjects with uncontrolled asthma. Overall adherence to controller medications was low, with no more than 50% of the subjects refilling the medication after the initial fill. For subjects with allergic rhinitis, the subjects in TennCare Medicaid treated with LTRAs were less likely to experience ED visits (hazard ratio 0.44 [95% CI, 0.21-0.93]) compared with the subjects treated with ICS. For all other groups, the subjects treated with LTRA or ICS-LABA were just as likely to experience ED visits or hospitalizations, or need oral corticosteroids as the subjects treated with ICS., Conclusion: Risks of asthma-related exacerbations did not differ between children who initiated LTRA and ICS. These findings may be explainable by LTRA, which has similar effectiveness as ICS in real-life usage by residual confounding by indication or other unmeasured factors., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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184. Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data.
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Mosley JD, Van Driest SL, Larkin EK, Weeke PE, Witte JS, Wells QS, Karnes JH, Guo Y, Bastarache L, Olson LM, McCarty CA, Pacheco JA, Jarvik GP, Carrell DS, Larson EB, Crosslin DR, Kullo IJ, Tromp G, Kuivaniemi H, Carey DJ, Ritchie MD, Denny JC, and Roden DM
- Subjects
- Electronic Health Records, Genetic Predisposition to Disease genetics, Humans, Phenotype, Polymorphism, Single Nucleotide genetics, Genome-Wide Association Study methods
- Abstract
A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
- Published
- 2013
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185. Statin exposure is associated with decreased asthma-related emergency department visits and oral corticosteroid use.
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Tse SM, Li L, Butler MG, Fung V, Kharbanda EO, Larkin EK, Vollmer WM, Miroshnik I, Rusinak D, Weiss ST, Lieu T, and Wu AC
- Subjects
- Administration, Oral, Adult, Aged, Asthma complications, Case-Control Studies, Cohort Studies, Disease Progression, Female, Hospitalization statistics & numerical data, Humans, Hyperlipidemias complications, Logistic Models, Male, Middle Aged, Odds Ratio, Propensity Score, Treatment Outcome, Adrenal Cortex Hormones therapeutic use, Asthma drug therapy, Emergency Service, Hospital statistics & numerical data, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hyperlipidemias drug therapy
- Abstract
Rationale: Statins, or HMG-CoA reductase inhibitors, may aid in the treatment of asthma through their pleiotropic antiinflammatory effects., Objectives: To examine the effect of statin therapy on asthma-related exacerbations using a large population-based cohort., Methods: Statin users aged 31 years or greater with asthma were identified from the Population-Based Effectiveness in Asthma and Lung population, which includes data from five health plans. Statin exposure and asthma exacerbations were assessed over a 24-month observation period. Statin users with a statin medication possession ratio greater than or equal to 80% were matched to non-statin users by age, baseline asthma therapy, site of enrollment, season at baseline, and propensity score, which was calculated based on patient demographics and Deyo-Charlson conditions. Asthma exacerbations were defined as two or more oral corticosteroid dispensings, asthma-related emergency department visits, or asthma-related hospitalizations. The association between statin exposure and each of the three outcome measures was assessed using conditional logistic regression., Measurements and Main Results: Of the 14,566 statin users, 8,349 statin users were matched to a nonuser. After adjusting for Deyo-Charlson conditions that remained unbalanced after matching, among statin users, statin exposure was associated with decreased odds of having asthma-related emergency department visits (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.53-0.77; P < 0.0001) and two or more oral corticosteroid dispensings (OR, 0.90; 95% CI, 0.81-0.99; P = 0.04). There were no differences in asthma-related hospitalizations (OR, 0.91; 95% CI, 0.66-1.24; P = 0.52)., Conclusions: Among statin users with asthma, statin exposure was associated with decreased odds of asthma-related emergency department visits and oral corticosteroid dispensings.
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- 2013
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186. Shorter survival in familial versus idiopathic pulmonary arterial hypertension is associated with hemodynamic markers of impaired right ventricular function.
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Brittain EL, Pugh ME, Wheeler LA, Robbins IM, Loyd JE, Newman JH, Larkin EK, Austin ED, and Hemnes AR
- Abstract
Abstract Although individuals with familial pulmonary arterial hypertension (FPAH) have more severe hemodynamics, compared to individuals with idiopathic PAH (IPAH), it is unclear whether this translates into a survival difference. The influence of right ventricular (RV) function on survival in these groups is also unknown. We reviewed hemodynamic data and health information from a prospective institutional database of 57 FPAH and 66 IPAH patients registered with the Vanderbilt Pulmonary Hypertension Research Cohort. We compared hemodynamics at the time of diagnosis between the two groups and calculated pulmonary arteriolar capacitance (PC) and RV stroke work index (RVSWI). Using survival analysis, we compared freedom from a 5-year composite of death or lung transplantation in FPAH and IPAH patients. The composite outcome of death or transplant at 5 years from diagnosis was significantly increased in FPAH (log rank [Formula: see text]). PC and RVSWI were significantly decreased in FPAH, compared to IPAH ([Formula: see text] for both). In univariate analysis, PC (odds ratio [OR]: 0.17 [95% confidence interval (95% CI): 0.03-0.83]) and RVSWI (OR: 0.86 [95% CI: 0.77-0.95]) were predictors of mortality, as were cardiac index (OR: 0.17 [95% CI: 0.06-0.51]) and PVR (OR: 1.1 [95% CI: 1.01-1.12]). Among FPAH patients, RVSWI was lower in those who died or received a transplant than in survivors ([Formula: see text]), while PC was not ([Formula: see text]). We found significantly worse event-free survival and significantly lower PC and RVSWI in FPAH than in IPAH. In FPAH patients who died or underwent transplantation, RVSWI was lower than that in survivors, suggesting disproportionate RV dysfunction.
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- 2013
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187. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension.
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Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA 3rd, Hamid R, and Loyd JE
- Subjects
- Adult, Age of Onset, Aged, Familial Primary Pulmonary Hypertension, Female, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Mutation genetics, Pedigree, Registries, Anticipation, Genetic, Bone Morphogenetic Protein Receptors, Type II genetics, Hypertension, Pulmonary genetics
- Abstract
Rationale: Analysis of the age of onset in heritable pulmonary arterial hypertension (HPAH) has led to the hypothesis that genetic anticipation causes younger age of onset and death in subsequent generations. With accrual of pedigree data over multiple decades, we retested this hypothesis using analyses that eliminate the truncation of data that exists with shorter duration of follow-up., Objectives: To analyze the pedigrees of families with mutations in bone morphogenetic protein receptor type 2 (BMPR2), afflicted in two or more generations with HPAH, eliminating time truncation bias by including families for whom we have at least 57 years of data., Methods: We analyzed 355 individuals with BMPR2 mutations from 53 families in the Vanderbilt Pulmonary Hypertension Registry. We compared age at diagnosis or death in affected individuals (n = 249) by generation within families with multigenerational disease. We performed linear mixed effects models and we limited time-truncation bias by restricting date of birth to before 1955. This allowed for 57 years of follow-up (1955-2012) for mutation carriers to develop disease. We also conducted Kaplan-Meier analysis to include currently unaffected mutation carriers (n = 106)., Measurements and Main Results: Differences in age at diagnosis by generation were found in a biased analysis that included all birth years to the present, but this finding was eliminated when the 57-year observation limit was imposed. By Kaplan-Meier analysis, inclusion of currently unaffected mutation carriers strengthens the observation that bias of ascertainment exists when recent generations are included., Conclusions: Genetic anticipation is likely an artifact of incomplete time of observation of kindreds with HPAH due to BMPR2 mutations.
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- 2012
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188. Relationship of maternal vitamin D level with maternal and infant respiratory disease.
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Carroll KN, Gebretsadik T, Larkin EK, Dupont WD, Liu Z, Van Driest S, and Hartert TV
- Subjects
- Adult, Black or African American, Female, Humans, Infant, Male, Risk Factors, Vitamin D blood, White People, Asthma blood, Bronchiolitis blood, Vitamin D analogs & derivatives
- Abstract
Objective: The objective of the study was to investigate the association of maternal vitamin D and maternal asthma and infant respiratory infection severity., Study Design: The study included cross-sectional analyses of 340 mother-infant dyads enrolled from September to May 2004-2008 during an infant viral respiratory infection. Maternal vitamin D levels were determined from enrollment blood specimens. At enrollment, we determined self-reported maternal asthma and infant respiratory infection severity using a bronchiolitis score. We assessed the association of maternal vitamin D levels and maternal asthma and infant bronchiolitis score in race-stratified multivariable regression models., Results: The cohort was 70% white, 19% African American, and 21% had asthma. Overall, the median maternal vitamin D level was 20 ng/mL (interquartile range, 14-28). Among white women, a 14 ng/mL increase in vitamin D was associated with a decreased odds of asthma (adjusted odds ratio, 0.54; 95% confidence interval, 0.33-0.86). Maternal vitamin D was not associated with infant bronchiolitis score., Conclusion: Higher maternal vitamin D levels were associated with decreased odds of asthma., (Copyright © 2011 Mosby, Inc. All rights reserved.)
- Published
- 2011
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189. The landscape of recombination in African Americans.
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Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K, Buxbaum SG, Akylbekova EL, Aldrich MC, Ambrosone CB, Amos C, Bandera EV, Berndt SI, Bernstein L, Blot WJ, Bock CH, Boerwinkle E, Cai Q, Caporaso N, Casey G, Cupples LA, Deming SL, Diver WR, Divers J, Fornage M, Gillanders EM, Glessner J, Harris CC, Hu JJ, Ingles SA, Isaacs W, John EM, Kao WH, Keating B, Kittles RA, Kolonel LN, Larkin E, Le Marchand L, McNeill LH, Millikan RC, Murphy A, Musani S, Neslund-Dudas C, Nyante S, Papanicolaou GJ, Press MF, Psaty BM, Reiner AP, Rich SS, Rodriguez-Gil JL, Rotter JI, Rybicki BA, Schwartz AG, Signorello LB, Spitz M, Strom SS, Thun MJ, Tucker MA, Wang Z, Wiencke JK, Witte JS, Wrensch M, Wu X, Yamamura Y, Zanetti KA, Zheng W, Ziegler RG, Zhu X, Redline S, Hirschhorn JN, Henderson BE, Taylor HA Jr, Price AL, Hakonarson H, Chanock SJ, Haiman CA, Wilson JG, Reich D, and Myers SR
- Subjects
- Africa, Western ethnology, Alleles, Amino Acid Motifs, Base Sequence, Chromosome Mapping, Europe ethnology, Evolution, Molecular, Female, Gene Frequency, Genetics, Population, Genomics, Haplotypes genetics, Histone-Lysine N-Methyltransferase chemistry, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Humans, Male, Molecular Sequence Data, Pedigree, Polymorphism, Single Nucleotide genetics, Probability, White People genetics, Black or African American genetics, Crossing Over, Genetic genetics, Genome, Human genetics
- Abstract
Recombination, together with mutation, gives rise to genetic variation in populations. Here we leverage the recent mixture of people of African and European ancestry in the Americas to build a genetic map measuring the probability of crossing over at each position in the genome, based on about 2.1 million crossovers in 30,000 unrelated African Americans. At intervals of more than three megabases it is nearly identical to a map built in Europeans. At finer scales it differs significantly, and we identify about 2,500 recombination hotspots that are active in people of West African ancestry but nearly inactive in Europeans. The probability of a crossover at these hotspots is almost fully controlled by the alleles an individual carries at PRDM9 (P value < 10(-245)). We identify a 17-base-pair DNA sequence motif that is enriched in these hotspots, and is an excellent match to the predicted binding target of PRDM9 alleles common in West Africans and rare in Europeans. Sites of this motif are predicted to be risk loci for disease-causing genomic rearrangements in individuals carrying these alleles. More generally, this map provides a resource for research in human genetic variation and evolution.
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- 2011
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190. Short duration of sleep increases risk of colorectal adenoma.
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Thompson CL, Larkin EK, Patel S, Berger NA, Redline S, and Li L
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- Female, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Sleep Apnea Syndromes complications, Sleep Disorders, Circadian Rhythm complications, Surveys and Questionnaires, Adenoma etiology, Colorectal Neoplasms etiology, Sleep, Sleep Deprivation
- Abstract
Background: Short duration and poor quality of sleep have been associated with increased risks of obesity, cardiovascular disease, diabetes mellitus, and total mortality. However, few studies have investigated their associations with risk of colorectal neoplasia., Methods: In a screening colonoscopy-based case-control study, the Pittsburg Sleep Quality Index (PSQI) was administered to 1240 study participants before colonoscopy., Results: Three hundred thirty-eight (27.3%) of the participants were diagnosed with incident colorectal adenomas. Although there was no appreciable difference in the overall PSQI score between cases and adenoma-free controls (5.32 vs 5.11; P = .37), the authors found a statistically significant association of colorectal adenoma with the PSQI component 3, which corresponds to sleep duration (P = .02). Cases were more likely to average less than 6 hours of sleep per night (28.9% vs 22.1% in controls, P = .01). In multivariate regression analysis adjusted for age, gender, race, smoking, family history of colorectal cancer, and waist-to-hip ratio, individuals averaging less than 6 hours per night had an almost 50% increase in risk of colorectal adenomas (OR = 1.47; CI = 1.05-2.06, P for trend = .02) as compared with individuals sleeping at least 7 hours per night. Cases were also more likely to report being diagnosed with sleep apnea (9.8% vs 6.5%, P = .05) and more likely to have worked alternate shifts (54.0% vs 46.1%, P = .01), although these differences were not significant in multivariate models., Conclusions: Shorter duration of sleep significantly increases risk of colorectal adenomas. The authors' results suggest sleep duration as a novel risk factor for colorectal neoplasia., (Copyright © 2010 American Cancer Society.)
- Published
- 2011
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191. Systems biology analyses of gene expression and genome wide association study data in obstructive sleep apnea.
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Liu Y, Patel S, Nibbe R, Maxwell S, Chowdhury SA, Koyuturk M, Zhu X, Larkin EK, Buxbaum SG, Punjabi NM, Gharib SA, Redline S, and Chance MR
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- Adipose Tissue metabolism, Algorithms, Case-Control Studies, Computational Biology, Gene Expression, Genome-Wide Association Study statistics & numerical data, Humans, Oligonucleotide Array Sequence Analysis statistics & numerical data, Polymorphism, Single Nucleotide, Protein Interaction Maps genetics, Signal Transduction genetics, Sleep Apnea, Obstructive metabolism, Systems Biology, Sleep Apnea, Obstructive genetics
- Abstract
The precise molecular etiology of obstructive sleep apnea (OSA) is unknown; however recent research indicates that several interconnected aberrant pathways and molecular abnormalities are contributors to OSA. Identifying the genes and pathways associated with OSA can help to expand our understanding of the risk factors for the disease as well as provide new avenues for potential treatment. Towards these goals, we have integrated relevant high dimensional data from various sources, such as genome-wide expression data (microarray), protein-protein interaction (PPI) data and results from genome-wide association studies (GWAS) in order to define sub-network elements that connect some of the known pathways related to the disease as well as define novel regulatory modules related to OSA. Two distinct approaches are applied to identify sub-networks significantly associated with OSA. In the first case we used a biased approach based on sixty genes/proteins with known associations with sleep disorders and/or metabolic disease to seed a search using commercial software to discover networks associated with disease followed by information theoretic (mutual information) scoring of the sub-networks. In the second case we used an unbiased approach and generated an interactome constructed from publicly available gene expression profiles and PPI databases, followed by scoring of the network with p-values from GWAS data derived from OSA patients to uncover sub-networks significant for the disease phenotype. A comparison of the approaches reveals a number of proteins that have been previously known to be associated with OSA or sleep. In addition, our results indicate a novel association of Phosphoinositide 3-kinase, the STAT family of proteins and its related pathways with OSA.
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- 2011
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192. Study of the relationship between the interleukin-6 gene and obstructive sleep apnea.
- Author
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Larkin EK, Patel SR, Zhu X, Tracy RP, Jenny NS, Reiner AP, Walston J, and Redline S
- Subjects
- Adult, Black or African American genetics, Alleles, Female, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide genetics, Interleukin-6 genetics, Sleep Apnea, Obstructive genetics
- Published
- 2010
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193. A candidate gene study of obstructive sleep apnea in European Americans and African Americans.
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Larkin EK, Patel SR, Goodloe RJ, Li Y, Zhu X, Gray-McGuire C, Adams MD, and Redline S
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Body Mass Index, C-Reactive Protein genetics, Case-Control Studies, Child, Child, Preschool, Genetic Association Studies, Glial Cell Line-Derived Neurotrophic Factor genetics, Humans, Linkage Disequilibrium, Logistic Models, Male, Middle Aged, Multivariate Analysis, Phenotype, Receptors, Serotonin genetics, Black or African American genetics, Polymorphism, Single Nucleotide, Sleep Apnea, Obstructive ethnology, Sleep Apnea, Obstructive genetics, White People genetics
- Abstract
Rationale: Obstructive sleep apnea (OSA) is hypothesized to be influenced by genes within pathways involved with obesity, craniofacial development, inflammation, and ventilatory control., Objectives: We conducted the first candidate gene study of OSA using family data from European Americans and African Americans, selecting biologically plausible genes from within these pathways., Methods: A total of 1,080 single nucleotide polymorphisms (SNPs) were genotyped in 729 African Americans and 505 SNPs were genotyped in 694 European Americans. Coding for SNPs additively, association testing on the apnea-hypopnea index (AHI) as a continuous trait, and OSA as a dichotomous trait (AHI ≥15) was conducted using methods that account for familial correlations in models adjusted for age, age-squared, and sex, with and without body mass index., Measurements and Main Results: In European Americans, variants within C-reactive protein (CRP) and glial cell line-derived neurotrophic factor (GDNF) were associated with AHI (CRP: β = 4.6; SE = 1.1; P = 0.0000402) (GDNF: β = 4.3; SE = 1; P = 0.0000201) and with the dichotomous OSA trait (CRP: odds ratio = 2.4; 95% confidence interval, 1.5-3.9; P = 0.000170) (GDNF: odds ratio = 2; 95% confidence interval, 1.4-2.89; P = 0.0000433). In African Americans, rs9526240 within serotonin receptor 2a (HTR2A: odds ratio = 2.1; 95% confidence interval, 1.5-2.9; P = 0.00005233) was associated with OSA., Conclusions: This candidate gene analysis identified the potential role of genes operating through intermediate disease pathways to influence sleep apnea phenotypes, providing a framework for focusing future replication studies.
- Published
- 2010
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194. Genome-wide linkage of obstructive sleep apnoea and high-density lipoprotein cholesterol in a Filipino family: bivariate linkage analysis of obstructive sleep apnoea.
- Author
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Relf BL, Larkin EK, De Torres C, Baur LA, Christodoulou J, and Waters KA
- Subjects
- Adult, Body Mass Index, Child, Cholesterol blood, Cholesterol, HDL blood, Chromosomes, Human, 19-20 genetics, Family, Female, Genetic Linkage genetics, Genotype, Humans, Insulin blood, Lod Score, Male, Phenotype, Polysomnography, Receptors, KIR genetics, Sleep genetics, Sleep physiology, Sleep Apnea, Obstructive blood, Triglycerides blood, Cholesterol, HDL genetics, Genome-Wide Association Study, Sleep Apnea, Obstructive genetics
- Abstract
Increasing evidence supports an association between obstructive sleep apnoea (OSA) and metabolic syndrome (MeS) in both children and adults, suggesting a genetic component. However, the genetic relationship between the diseases remains unclear. We performed a bivariate linkage scan on a single Filipino family with a high prevalence of OSA and MeS to explore the genetic pathways underlying these diseases. A large rural family (n = 50, 50% adults) underwent a 10-cM genome-wide scan. Fasting blood was used to measure insulin, triglycerides, total cholesterol and high density lipoprotein (HDL) cholesterol. Attended overnight polysomnography was used to quantify the respiratory disturbance index (RDI), a measure of sleep apnoea. Body mass index z-scores and insulin resistance scores were calculated. Bivariate multipoint linkage analyses were performed on RDI and MeS components. OSA prevalence was 46% (n = 23; nine adults, 14 children) in our participants. MeS phenotype was present in 40% of adults (n = 10) and 48% of children (n = 12). Linkage peaks with a logarithm of odds (LOD) score >3 were demonstrated on chromosome 19q13.4 (LOD = 3.04) for the trait pair RDI and HDL cholesterol. Candidate genes identified in this region include the killer cell immunoglobulin-like receptor genes. These genes are associated with modulating inflammatory responses in reaction to cellular stress and initiation of atherosclerotic plaque formation. We have identified a novel locus for genetic links between RDI and lipid factors associated with MeS in a chromosomal region containing genes associated with inflammatory responses.
- Published
- 2010
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195. Discussing gene-gene interaction: warning--translating equations to English may result in jabberwocky.
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Bartlett CW, Vieland VJ, Bartlett J, Bell JT, Bhattacharjee S, Clerget-Darpoux F, Bush WS, Edwards TL, Gao G, Halder I, Huang Y, Kotti S, Larkin EK, Li H, Motsinger AA, Mukhopadhyay N, Namkung J, Park T, Ritchie MD, Stein CM, and Zhou JY
- Subjects
- Alleles, Case-Control Studies, Genetic Linkage, Humans, Models, Genetic, Polymorphism, Single Nucleotide, Epistasis, Genetic
- Abstract
Interest in mapping susceptibility alleles for complex diseases, which do not follow a classic single-gene segregation pattern, has driven interest in methods that account for, or use information from one locus when mapping another. Our discussion group examined methods related to epistasis or gene x gene interaction. The goal of modeling gene x gene interaction varied across groups; some papers tried to detect gene x gene interaction while others tried to exploit it to map genes. Most of the 10 papers summarized here applied newly created or newly modified statistical methods related to gene x gene interaction, while two groups primarily examined computational issues. As is often the case, comparisons are complicated by little overlap in the data used across the papers, and further complicated by the fact that the available data may not have been ideal for some gene x gene interaction methods. However, the main difficulty in comparing and contrasting methods across the papers is the lack of a consistent statistical definition of gene x gene interaction. But despite these issues, two clear trends emerged across the analyses: First, the methods for quantitative trait gene x gene interaction appeared to perform very well, even in families initially ascertained as affected sib pairs; and second, dichotomous trait gene x gene interaction methods failed to produce consistent results. The difficulty of using (primarily) affected sib pair data in a gene x gene interaction analysis is explored., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2007
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196. Modeling the complex gene x environment interplay in the simulated rheumatoid arthritis GAW15 data using latent variable structural equation modeling.
- Author
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Nock NL, Larkin EK, Morris NJ, Li Y, and Stein CM
- Abstract
Rheumatoid arthritis is a complex disease that appears to involve multiple genetic and environmental factors. Using the Genetic Analysis Workshop 15 simulated rheumatoid arthritis data and the structural equation modeling framework, we tested hypothesized "causal" rheumatoid arthritis model(s) by employing a novel latent gene construct approach that models individual genes as latent variables defined by multiple dense and non-dense single-nucleotide polymorphisms (SNPs). Our approach produced valid latent gene constructs, particularly with dense SNPs, which when coupled with other factors involved in rheumatoid arthritis, were able to generate good fitting models by certain goodness of fit indices. We observed that Gene F, C, DR, sex and smoking were significant predictors of rheumatoid arthritis but Genes A and E were not, which was generally, but not entirely, consistent with how the data were simulated. Our approach holds promise in unravelling complex diseases and improves upon current "one SNP (haplotype)-at-a-time" regression approaches by decreasing the number of statistical tests while minimizing problems with multicolinearity and haplotype estimation algorithm error. Furthermore, when genes are modeled as latent constructs simultaneously with other key cofactors, the approach provides enhanced control of confounding that should lead to less biased effect estimates among genes as well as between gene(s) and the complex disease. However, further study is needed to quantify bias, evaluate fit index disparity, and resolve multiplicative latent gene interactions. Moreover, because some a priori biological information is needed to form an initial substantive model, our approach may be most appropriate for candidate gene SNP panel applications.
- Published
- 2007
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197. Comparison of affected sibling-pair linkage methods to identify gene x gene interaction in GAW15 simulated data.
- Author
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Larkin EK, Morris NJ, Li Y, Nock NL, and Stein CM
- Abstract
Non-parametric linkage methods have had limited success in detecting gene by gene interactions. Using affected sibling-pair (ASP) data from all replicates of the simulated data from Problem 3, we assessed the statistical power of three approaches to identify the gene x gene interaction between two loci on different chromosomes. The first method conditioned on linkage at the primary disease susceptibility locus (DR), to find linkage to a simulated effect modifier at Locus A with a mean allele sharing test. The second approach used a regression-based mean test to identify either the presence of interaction between the two loci or linkage to the A locus in the presence of linkage to DR. The third method applied a conditional logistic model designed to test for the presence of interacting loci. The first approach had decreased power over an unconditional linkage analysis, supporting the idea that gene x gene interaction cannot be detected with ASP data. The regression-based mean test and the conditional logistic model had the lowest power to detect gene x gene interaction, possibly because of the complex recoding of the tri-allelic DR locus for use as a covariate. We conclude that the ASP approaches tested have low power to successfully identify the interaction between the DR and A loci despite the large sample size, which may be due to the low prevalence of the high-risk DR genotypes. Additionally, the lack of data on discordant sibships may have decreased the power to identify gene x gene interactions.
- Published
- 2007
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- View/download PDF
198. Self-reported race and genetic admixture.
- Author
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Sinha M, Larkin EK, Elston RC, and Redline S
- Subjects
- Humans, Pharmacogenetics, Self-Assessment, Black People genetics, Racial Groups, White People genetics
- Published
- 2006
- Full Text
- View/download PDF
199. Incidence of sleep-disordered breathing in an urban adult population: the relative importance of risk factors in the development of sleep-disordered breathing.
- Author
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Tishler PV, Larkin EK, Schluchter MD, and Redline S
- Subjects
- Adult, Body Mass Index, Cholesterol blood, Female, Humans, Incidence, Male, Middle Aged, Regression Analysis, Risk Factors, Sleep Apnea Syndromes blood, Sleep Apnea Syndromes diagnosis, Urban Population, Sleep Apnea Syndromes epidemiology
- Abstract
Context: Sleep-disordered breathing (SDB) is both prevalent and associated with serious chronic illness. The incidence of SDB and the effect of risk factors on this incidence are unknown., Objective: To determine the 5-year incidence of SDB overall and as influenced by risk factors., Design, Setting, and Participants: Of the 1149 participants in the Cleveland Family Study, those aged 18 years or older, from either case or control families, who had 2 in-home sleep studies 5 years apart. The first had to have been performed before June 30, 1997, and had to have normal results (apnea hypopnea index [AHI] <5). Data included questionnaire information on medical and family history, SDB symptoms; measurement of height, weight, blood pressure, waist and hip circumference, and serum cholesterol concentration; and overnight sleep monitoring., Main Outcome Measure: Apnea hypopnea index, defined as number of apneas and hypopneas per hour of sleep. Sleep-disordered breathing was defined by an AHI of at least 10 (mild to moderate) or of at least 15 (moderate)., Results: Forty-seven (16%) of 286 eligible participants, (95% confidence interval [CI], 13%-21%) had a second-study AHI of at least 10 and 29 (10%) participants (95% CI, 7%-14%) had a second-study AHI result of at least 15. For the AHI results of at least 15, we estimate that about 2.5% may represent test variability. By ordinal logistic regression analysis, AHI was significantly associated with age (odds ratio [OR] per 10-year increase, 1.79; 95% CI, 1.41-2.27), body mass index (BMI; OR per 1-unit increase, 1.14; 95% CI, 1.10-1.19), sex (OR for men vs women, 4.12; 95% CI, 2.29-7.43), waist-hip ratio (OR per 0.1 unit increase, 1.61; 95% CI, 1.04-2.28), and serum cholesterol concentration (OR per 10-mg/dL [0.25-mmol/L] increase, 1.11; 95% CI, 1.03-1.19). Interactions were noted between age and both sex (P =.003) and BMI (P =.05). The OR for increased AHI per 10-year age increase was 2.41 in women (95% CI, 1.78-3.26) and 1.15 in men (95% CI, 0.78-1.68), with the male vs female OR decreasing from 5.04 (95% CI, 2.19-11.6) at age 30 years to 0.54 (95% CI, 0.15-1.99) at age 60 years. The OR for increased AHI per 1-unit increase in BMI decreased from 1.21 (95% CI, 1.11-1.31) at age 20 years to 1.05 (95% CI, 0.96-1.15) at age 60 years., Conclusions: The 5-year incidence is about 7.5% for moderately severe SDB and 16% (or less) for mild to moderately severe SDB. Incidence of SDB is influenced independently by age, sex, BMI, waist-hip ratio, and serum cholesterol concentration. Predominance in men diminishes with increasing age, and by age 50 years, incidence rates among men and women are similar. The effect of BMI also decreases with age and may be negligible at age 60 years.
- Published
- 2003
- Full Text
- View/download PDF
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