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1.  Prevalence of Diabetes Among Hispanics/Latinos From Diverse Backgrounds: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) 
Diabetes Care  2014;37(8):2233-2239.
OBJECTIVE
We examine differences in prevalence of diabetes and rates of awareness and control among adults from diverse Hispanic/Latino backgrounds in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).
RESEARCH DESIGN AND METHODS
The HCHS/SOL, a prospective, multicenter, population-based study, enrolled from four U.S. metropolitan areas from 2008 to 2011 16,415 18–74-year-old people of Hispanic/Latino descent. Diabetes was defined by either fasting plasma glucose, impaired glucose tolerance 2 h after a glucose load, glycosylated hemoglobin (A1C), or documented use of hypoglycemic agents (scanned medications).
RESULTS
Diabetes prevalence varied from 10.2% in South Americans and 13.4% in Cubans to 17.7% in Central Americans, 18.0% in Dominicans and Puerto Ricans, and 18.3% in Mexicans (P < 0.0001). Prevalence related positively to age (P < 0.0001), BMI (P < 0.0001), and years living in the U.S. (P = 0.0010) but was negatively related to education (P = 0.0005) and household income (P = 0.0043). Rate of diabetes awareness was 58.7%, adequate glycemic control (A1C <7%, 53 mmol/mol) was 48.0%, and having health insurance among those with diabetes was 52.4%.
CONCLUSIONS
Present findings indicate a high prevalence of diabetes but considerable diversity as a function of Hispanic background. The low rates of diabetes awareness, diabetes control, and health insurance in conjunction with the negative associations between diabetes prevalence and both household income and education among Hispanics/Latinos in the U.S. have important implications for public health policies.
doi:10.2337/dc13-2939
PMCID: PMC4113173  PMID: 25061138
2.  Circulating IGF-axis Protein Levels and Their Relation with Levels of Plasma Adipocytokines and Macronutrient Consumption in Women 
Objective
Circulating free insulin-like growth factor (IGF)-I and its binding proteins, most notably, IGFBP-1 and IGFBP-2, have been prospectively associated with incident type 2 diabetes in women. However, little is known regarding the factors that may influence these IGF-axis protein levels. To study the relation of IGF-axis protein levels with adipocytokines, macronutrient consumption, and other factors related to diabetes.
Design
Fasting plasma from 558 controls enrolled in a nested case-control study within the Nurses’ Health Study of incident type 2 diabetes in women were tested for: IGF-axis proteins (free and total IGF-I, IGFBP-1, IGFBP-2, IGFBP-3), adipocytokines (leptin, adiponectin, resistin), soluble leptin receptor (sOB-R), inflammatory factors (IL-18 and C-reactive protein (CRP)), insulin, and glycated hemoglobin (HbA1C).
Results
In multivariate models, each 1% increase in sOB-R (mean 34.9 ng/mL, standard deviation (SD) ±11.3) was associated with −0.20% total IGF-I (P=0.0003) and −0.42% free IGF-I (P=0.002), as well as 0.73% higher IGFBP-1 (P<0.0001) and 0.27% IGFBP-2 (P=0.003). For example, a one SD change from the mean sOB-R level was associated with 11% lower free IGF-I. Insulin levels (mean 6.8 μU/mL ±5.3) were inversely and adiponectin (mean 18.3 μg/mL ±7.4) positively associated with IGFBP-1 and IGFBP-2 (all P<0.01). Consumption of dairy protein, monounsaturated fats, and saturated fats, was also correlated with IGF-axis protein levels (all P<0.05).
Conclusions
Several molecular factors and macronutrients were independently associated with plasma IGF-axis protein levels. Which of these, if any, reflect biologic relationships that can be intervened upon to influence IGF-axis protein concentrations warrants further investigation.
doi:10.1016/j.ghir.2014.04.006
PMCID: PMC4190839  PMID: 24888819
IGF-I; free IGF-I; IGFBP-1; IGFBP-2; IGFBP-3; adipocytokines; macronutrients
3.  Prevalence of Metabolic Syndrome Among Hispanics/Latinos of Diverse Background: The Hispanic Community Health Study/Study of Latinos 
Diabetes Care  2014;37(8):2391-2399.
OBJECTIVE
Approximately one-third of the adult U.S. population has the metabolic syndrome. Its prevalence is the highest among Hispanic adults, but variation by Hispanic/Latino background is unknown. Our objective was to quantify the prevalence of the metabolic syndrome among men and women 18–74 years of age of diverse Hispanic/Latino background.
RESEARCH DESIGN AND METHODS
Two-stage area probability sample of households in four U.S. locales, yielding 16,319 adults (52% women) who self-identified as Cuban, Dominican, Mexican, Puerto Rican, Central American, or South American. The metabolic syndrome was defined according to the American Heart Association/National Heart, Lung, and Blood Institute 2009 Joint Scientific Statement. The main outcome measures were age-standardized prevalence of the metabolic syndrome per the harmonized American Heart Association/National Heart, Lung, and Blood Institute definition and its component abnormalities.
RESULTS
The metabolic syndrome was present in 36% of women and 34% of men. Differences in the age-standardized prevalence were seen by age, sex, and Hispanic/Latino background. The prevalence of the metabolic syndrome among those 18–44, 45–64, and 65–74 years of age was 23%, 50%, and 62%, respectively, among women; and 25%, 43%, and 55%, respectively, among men. Among women, the metabolic syndrome prevalence ranged from 27% in South Americans to 41% in Puerto Ricans. Among men, prevalences ranged from 27% in South Americans to 35% in Cubans. In those with the metabolic syndrome, abdominal obesity was present in 96% of the women compared with 73% of the men; more men (73%) than women (62%) had hyperglycemia.
CONCLUSIONS
The burden of cardiometabolic abnormalities is high in Hispanic/Latinos but varies by age, sex, and Hispanic/Latino background. Hispanics/Latinos are thus at increased, but modifiable, predicted lifetime risk of diabetes and its cardiovascular sequelae.
doi:10.2337/dc13-2505
PMCID: PMC4113166  PMID: 25061141
4.  Genetic Variants Related to Height and Risk of Atrial Fibrillation 
American Journal of Epidemiology  2014;180(2):215-222.
Increased height is a known independent risk factor for atrial fibrillation (AF). However, whether genetic determinants of height influence risk is uncertain. In this candidate gene study, we examined the association of 209 height-associated single-nucleotide polymorphisms (SNPs) with incident AF in 3,309 persons of European descent from the Cardiovascular Health Study, a prospective cohort study of older adults (aged ≥65 years) enrolled in 1989–1990. After a median follow-up period of 13.2 years, 879 participants developed incident AF. The height-associated SNPs together explained approximately 10% of the variation in height (P = 6.0 × 10−8). Using an unweighted genetic height score, we found a nonsignificant association with risk of AF (per allele, hazard ratio = 1.01, 95% confidence interval: 1.00, 1.02; P = 0.06). In weighted analyses, we found that genetically predicted height was strongly associated with AF risk (per 10 cm, hazard ratio = 1.30, 95% confidence interval: 1.03, 1.64; P = 0.03). Importantly, for all models, the inclusion of actual height completely attenuated the genetic height effect. Finally, we identified 1 nonsynonymous SNP (rs1046934) that was independently associated with AF and may warrant future study. In conclusion, we found that genetic determinants of height appear to increase the risk of AF, primarily via height itself. This approach of examining SNPs associated with an intermediate phenotype should be considered as a method for identifying novel genetic targets.
doi:10.1093/aje/kwu126
PMCID: PMC4082343  PMID: 24944287
atrial fibrillation; cardiovascular disease; genetics; risk factors; risk prediction
5.  Dietary Protein Intake and Change in Estimated GFR in the Cardiovascular Health Study 
Objective
With aging, kidney function declines, as evidenced by reduced glomerular filtration rate. It is controversial whether or not high protein intake accelerates the kidney function decline.
Research Methods & Procedures
We examined whether dietary protein is associated with change in kidney function (mean follow-up 6.4 (SD=1.4, range = 2.5 to 7.9) years in the Cardiovascular Health Study (n =3,623). We estimated protein intake using a food frequency questionnaire (FFQ) and estimated glomerular filtration rate (eGFR) from cystatin C. Associations between protein intake and kidney function were determined by linear and logistic regression models.
Results
Average protein intake was 19% of energy intake (SD=5%). Twenty-seven percent (n=963) of study participants had rapid decline in kidney function, as defined by (ΔeGFRcysC > 3 mL/min per 1.73 m2). Protein intake (characterized as g/day and % energy/day), was not associated with change in eGFR (P>0.05 for all comparisons). There were also no significant associations when protein intake was separated by source (animal and vegetable).
Conclusion
These data suggest that higher protein intake does not have a major impact on kidney function decline among elderly men and women.
doi:10.1016/j.nut.2013.12.006
PMCID: PMC4082792  PMID: 24984995
kidney; glomerular filtration rate; vegetable protein; animal protein; macronutrients
6.  Prevalence of Hypertension, Awareness, Treatment, and Control in the Hispanic Community Health Study/Study of Latinos 
American Journal of Hypertension  2014;27(6):793-800.
BACKGROUND
The prevention and control of hypertension is an essential component for reducing the burden of cardiovascular diseases. Here we describe the prevalence of hypertension in diverse Hispanic/Latino background groups and describe the proportion who are aware of their diagnosis, receiving treatment, and having their hypertension under control.
METHODS
The Hispanic Community Health Study/Study of Latinos is a longitudinal cohort study of 16,415 Hispanics/Latinos, aged 18–74 years from 4 US communities (Bronx, NY; Chicago, IL; Miami, FL; and San Diego, CA). At baseline (2008–2011) the study collected extensive measurements and completed questionnaires related to research on cardiovascular diseases. Hypertension was defined as measured blood pressure ≥140/90mm Hg or use of antihypertensive medication.
RESULTS
The total age-adjusted prevalence of hypertension in this study was 25.5% as compared with 27.4% in non-Hispanic whites in the National Health and Nutrition Examination Survey. Prevalence of hypertension increased with increasing age groups and was highest in Cuban, Puerto Rican, and Dominican background groups. The percent with hypertension who were aware, being treated with medication, or had their hypertension controlled was lower compared with US non-Hispanic whites with hypertension and it was lowest in those without health insurance.
CONCLUSIONS
These findings indicate a significant deficit in treatment and control of hypertension among Hispanics/Latinos residing in the United States, particularly those without health insurance. Given the relative ease of identification of hypertension and the availability of low-cost medications, enabling better access to diagnostic and treatment services should reduce the burden of hypertension in Hispanic populations.
doi:10.1093/ajh/hpu003
PMCID: PMC4017932  PMID: 24627442
blood pressure; epidemiology; Hispanics; hypertension; Latinos; medically uninsured; socioeconomic status.
7.  Post-transfusion purpura: a rare and life-threatening aetiology of thrombocytopenia 
BMJ Case Reports  2013;2013:bcr2013008860.
We present a middle-aged man with history of lung adenocarcinoma, who was admitted with massive haemoptysis secondary to severe thrombocytopenia. Two weeks prior he was started on enoxaparin for a newly diagnosed pulmonary embolus and at that time required blood transfusions for anaemia. Our initial diagnosis was heparin-induced thrombocytopenia. His platelet count, however, did not improve despite receiving argatroban and platelet transfusions. Hence, we suspected post-transfusion purpura (PTP) and started him on intravenous immunoglobulin which brought his platelet count to normal levels. The serotonin-release assay was negative and platelet-antibody test was positive confirming PTP as our diagnosis. The patient eventually was transferred to hospice care because of the advanced stage lung cancer and died of respiratory failure.
doi:10.1136/bcr-2013-008860
PMCID: PMC3669804  PMID: 23709534
8.  Prevalence of Hepatitis C Virus Infection in US Hispanic/Latino Adults: Results From the NHANES 2007–2010 and HCHS/SOL Studies 
The Journal of Infectious Diseases  2014;209(10):1585-1590.
Prevalence of hepatitis C virus (HCV) antibody has been reported in Mexican Americans, but its prevalence in other US Hispanic/Latino groups is unknown. We studied 2 populations of US Hispanic/Latino adults; 3210 from the National Health and Nutrition Examination Survey (NHANES) 2007–2010 and 11 964 from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Age-standardized prevalence of HCV antibody was similar in NHANES 2007–2010 (1.5%) and HCHS/SOL (2.0%) but differed significantly by Hispanic/Latino background in HCHS/SOL (eg, 11.6% in Puerto Rican men vs 0.4% in South American men). These findings suggest that the HCV epidemic among US Hispanics/Latinos is heterogeneous.
doi:10.1093/infdis/jit672
PMCID: PMC3997577  PMID: 24423693
hepatitis C virus; HCV; Hispanic; Latino; United States; prevalence; antibody; RNA; risk factor
9.  Macrophage inflammatory markers are associated with subclinical carotid artery disease in women with HIV or HCV infection 
Objective
Infection with hepatitis C (HCV) or human immunodeficiency virus (HIV) may be associated with atherosclerosis and vascular disease. Macrophages are a major component of atherosclerotic plaque, and classically activated (M1) macrophages contribute to plaque instability. Our goal was to identify plasma biomarkers that reflect macrophage inflammation and are associated with subclinical atherosclerosis.
Approach and results
We tested whether M1 macrophages produce galectin-3 binding protein (Gal-3BP) in-vitro. Then we measured Gal-3BP and the soluble macrophage biomarkers sCD163 and sCD14 in 264 participants in the Women’s Interagency HIV Study. Women were positive for HIV, HCV, both, or neither (66 in each group, matched for age, race/ethnicity and smoking status). Carotid artery disease was assessed by ultrasound measurement of right distal common carotid artery intima-media thickness (cIMT), distensibility, and presence of atherosclerotic lesions (IMT>1.5 mm). Plasma Gal-3BP was higher in HCV+ than HCV− women (p<0.01), but did not differ by HIV status. The three inflammatory macrophage markers were significantly correlated with each other and negatively correlated with CD4+ counts in HIV-infected women. We defined a macrophage score as 1, 2 or 3 biomarkers elevated above the median. In models adjusted for traditional risk factors, higher macrophage scores were significantly associated with increased atherosclerotic lesions and lower carotid distensibility. Receiver-operator curve analysis of lesions revealed that the markers added predictive value beyond traditional risk factors and C-reactive protein.
Conclusions
The macrophage inflammatory markers Gal-3BP, sCD163 and sCD14 are significantly associated with carotid artery disease in the setting of HIV and HCV infection.
doi:10.1161/ATVBAHA.113.303153
PMCID: PMC4067091  PMID: 24651679
atherosclerosis; women; AIDS; immune system; risk factors
10.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
11.  Defining the role of common variation in the genomic and biological architecture of adult human height 
Wood, Andrew R | Esko, Tonu | Yang, Jian | Vedantam, Sailaja | Pers, Tune H | Gustafsson, Stefan | Chu, Audrey Y | Estrada, Karol | Luan, Jian’an | Kutalik, Zoltán | Amin, Najaf | Buchkovich, Martin L | Croteau-Chonka, Damien C | Day, Felix R | Duan, Yanan | Fall, Tove | Fehrmann, Rudolf | Ferreira, Teresa | Jackson, Anne U | Karjalainen, Juha | Lo, Ken Sin | Locke, Adam E | Mägi, Reedik | Mihailov, Evelin | Porcu, Eleonora | Randall, Joshua C | Scherag, André | Vinkhuyzen, Anna AE | Westra, Harm-Jan | Winkler, Thomas W | Workalemahu, Tsegaselassie | Zhao, Jing Hua | Absher, Devin | Albrecht, Eva | Anderson, Denise | Baron, Jeffrey | Beekman, Marian | Demirkan, Ayse | Ehret, Georg B | Feenstra, Bjarke | Feitosa, Mary F | Fischer, Krista | Fraser, Ross M | Goel, Anuj | Gong, Jian | Justice, Anne E | Kanoni, Stavroula | Kleber, Marcus E | Kristiansson, Kati | Lim, Unhee | Lotay, Vaneet | Lui, Julian C | Mangino, Massimo | Leach, Irene Mateo | Medina-Gomez, Carolina | Nalls, Michael A | Nyholt, Dale R | Palmer, Cameron D | Pasko, Dorota | Pechlivanis, Sonali | Prokopenko, Inga | Ried, Janina S | Ripke, Stephan | Shungin, Dmitry | Stancáková, Alena | Strawbridge, Rona J | Sung, Yun Ju | Tanaka, Toshiko | Teumer, Alexander | Trompet, Stella | van der Laan, Sander W | van Setten, Jessica | Van Vliet-Ostaptchouk, Jana V | Wang, Zhaoming | Yengo, Loïc | Zhang, Weihua | Afzal, Uzma | Ärnlöv, Johan | Arscott, Gillian M | Bandinelli, Stefania | Barrett, Amy | Bellis, Claire | Bennett, Amanda J | Berne, Christian | Blüher, Matthias | Bolton, Jennifer L | Böttcher, Yvonne | Boyd, Heather A | Bruinenberg, Marcel | Buckley, Brendan M | Buyske, Steven | Caspersen, Ida H | Chines, Peter S | Clarke, Robert | Claudi-Boehm, Simone | Cooper, Matthew | Daw, E Warwick | De Jong, Pim A | Deelen, Joris | Delgado, Graciela | Denny, Josh C | Dhonukshe-Rutten, Rosalie | Dimitriou, Maria | Doney, Alex SF | Dörr, Marcus | Eklund, Niina | Eury, Elodie | Folkersen, Lasse | Garcia, Melissa E | Geller, Frank | Giedraitis, Vilmantas | Go, Alan S | Grallert, Harald | Grammer, Tanja B | Gräßler, Jürgen | Grönberg, Henrik | de Groot, Lisette C.P.G.M. | Groves, Christopher J | Haessler, Jeffrey | Hall, Per | Haller, Toomas | Hallmans, Goran | Hannemann, Anke | Hartman, Catharina A | Hassinen, Maija | Hayward, Caroline | Heard-Costa, Nancy L | Helmer, Quinta | Hemani, Gibran | Henders, Anjali K | Hillege, Hans L | Hlatky, Mark A | Hoffmann, Wolfgang | Hoffmann, Per | Holmen, Oddgeir | Houwing-Duistermaat, Jeanine J | Illig, Thomas | Isaacs, Aaron | James, Alan L | Jeff, Janina | Johansen, Berit | Johansson, Åsa | Jolley, Jennifer | Juliusdottir, Thorhildur | Junttila, Juhani | Kho, Abel N | Kinnunen, Leena | Klopp, Norman | Kocher, Thomas | Kratzer, Wolfgang | Lichtner, Peter | Lind, Lars | Lindström, Jaana | Lobbens, Stéphane | Lorentzon, Mattias | Lu, Yingchang | Lyssenko, Valeriya | Magnusson, Patrik KE | Mahajan, Anubha | Maillard, Marc | McArdle, Wendy L | McKenzie, Colin A | McLachlan, Stela | McLaren, Paul J | Menni, Cristina | Merger, Sigrun | Milani, Lili | Moayyeri, Alireza | Monda, Keri L | Morken, Mario A | Müller, Gabriele | Müller-Nurasyid, Martina | Musk, Arthur W | Narisu, Narisu | Nauck, Matthias | Nolte, Ilja M | Nöthen, Markus M | Oozageer, Laticia | Pilz, Stefan | Rayner, Nigel W | Renstrom, Frida | Robertson, Neil R | Rose, Lynda M | Roussel, Ronan | Sanna, Serena | Scharnagl, Hubert | Scholtens, Salome | Schumacher, Fredrick R | Schunkert, Heribert | Scott, Robert A | Sehmi, Joban | Seufferlein, Thomas | Shi, Jianxin | Silventoinen, Karri | Smit, Johannes H | Smith, Albert Vernon | Smolonska, Joanna | Stanton, Alice V | Stirrups, Kathleen | Stott, David J | Stringham, Heather M | Sundström, Johan | Swertz, Morris A | Syvänen, Ann-Christine | Tayo, Bamidele O | Thorleifsson, Gudmar | Tyrer, Jonathan P | van Dijk, Suzanne | van Schoor, Natasja M | van der Velde, Nathalie | van Heemst, Diana | van Oort, Floor VA | Vermeulen, Sita H | Verweij, Niek | Vonk, Judith M | Waite, Lindsay L | Waldenberger, Melanie | Wennauer, Roman | Wilkens, Lynne R | Willenborg, Christina | Wilsgaard, Tom | Wojczynski, Mary K | Wong, Andrew | Wright, Alan F | Zhang, Qunyuan | Arveiler, Dominique | Bakker, Stephan JL | Beilby, John | Bergman, Richard N | Bergmann, Sven | Biffar, Reiner | Blangero, John | Boomsma, Dorret I | Bornstein, Stefan R | Bovet, Pascal | Brambilla, Paolo | Brown, Morris J | Campbell, Harry | Caulfield, Mark J | Chakravarti, Aravinda | Collins, Rory | Collins, Francis S | Crawford, Dana C | Cupples, L Adrienne | Danesh, John | de Faire, Ulf | den Ruijter, Hester M | Erbel, Raimund | Erdmann, Jeanette | Eriksson, Johan G | Farrall, Martin | Ferrannini, Ele | Ferrières, Jean | Ford, Ian | Forouhi, Nita G | Forrester, Terrence | Gansevoort, Ron T | Gejman, Pablo V | Gieger, Christian | Golay, Alain | Gottesman, Omri | Gudnason, Vilmundur | Gyllensten, Ulf | Haas, David W | Hall, Alistair S | Harris, Tamara B | Hattersley, Andrew T | Heath, Andrew C | Hengstenberg, Christian | Hicks, Andrew A | Hindorff, Lucia A | Hingorani, Aroon D | Hofman, Albert | Hovingh, G Kees | Humphries, Steve E | Hunt, Steven C | Hypponen, Elina | Jacobs, Kevin B | Jarvelin, Marjo-Riitta | Jousilahti, Pekka | Jula, Antti M | Kaprio, Jaakko | Kastelein, John JP | Kayser, Manfred | Kee, Frank | Keinanen-Kiukaanniemi, Sirkka M | Kiemeney, Lambertus A | Kooner, Jaspal S | Kooperberg, Charles | Koskinen, Seppo | Kovacs, Peter | Kraja, Aldi T | Kumari, Meena | Kuusisto, Johanna | Lakka, Timo A | Langenberg, Claudia | Le Marchand, Loic | Lehtimäki, Terho | Lupoli, Sara | Madden, Pamela AF | Männistö, Satu | Manunta, Paolo | Marette, André | Matise, Tara C | McKnight, Barbara | Meitinger, Thomas | Moll, Frans L | Montgomery, Grant W | Morris, Andrew D | Morris, Andrew P | Murray, Jeffrey C | Nelis, Mari | Ohlsson, Claes | Oldehinkel, Albertine J | Ong, Ken K | Ouwehand, Willem H | Pasterkamp, Gerard | Peters, Annette | Pramstaller, Peter P | Price, Jackie F | Qi, Lu | Raitakari, Olli T | Rankinen, Tuomo | Rao, DC | Rice, Treva K | Ritchie, Marylyn | Rudan, Igor | Salomaa, Veikko | Samani, Nilesh J | Saramies, Jouko | Sarzynski, Mark A | Schwarz, Peter EH | Sebert, Sylvain | Sever, Peter | Shuldiner, Alan R | Sinisalo, Juha | Steinthorsdottir, Valgerdur | Stolk, Ronald P | Tardif, Jean-Claude | Tönjes, Anke | Tremblay, Angelo | Tremoli, Elena | Virtamo, Jarmo | Vohl, Marie-Claude | Amouyel, Philippe | Asselbergs, Folkert W | Assimes, Themistocles L | Bochud, Murielle | Boehm, Bernhard O | Boerwinkle, Eric | Bottinger, Erwin P | Bouchard, Claude | Cauchi, Stéphane | Chambers, John C | Chanock, Stephen J | Cooper, Richard S | de Bakker, Paul IW | Dedoussis, George | Ferrucci, Luigi | Franks, Paul W | Froguel, Philippe | Groop, Leif C | Haiman, Christopher A | Hamsten, Anders | Hayes, M Geoffrey | Hui, Jennie | Hunter, David J. | Hveem, Kristian | Jukema, J Wouter | Kaplan, Robert C | Kivimaki, Mika | Kuh, Diana | Laakso, Markku | Liu, Yongmei | Martin, Nicholas G | März, Winfried | Melbye, Mads | Moebus, Susanne | Munroe, Patricia B | Njølstad, Inger | Oostra, Ben A | Palmer, Colin NA | Pedersen, Nancy L | Perola, Markus | Pérusse, Louis | Peters, Ulrike | Powell, Joseph E | Power, Chris | Quertermous, Thomas | Rauramaa, Rainer | Reinmaa, Eva | Ridker, Paul M | Rivadeneira, Fernando | Rotter, Jerome I | Saaristo, Timo E | Saleheen, Danish | Schlessinger, David | Slagboom, P Eline | Snieder, Harold | Spector, Tim D | Strauch, Konstantin | Stumvoll, Michael | Tuomilehto, Jaakko | Uusitupa, Matti | van der Harst, Pim | Völzke, Henry | Walker, Mark | Wareham, Nicholas J | Watkins, Hugh | Wichmann, H-Erich | Wilson, James F | Zanen, Pieter | Deloukas, Panos | Heid, Iris M | Lindgren, Cecilia M | Mohlke, Karen L | Speliotes, Elizabeth K | Thorsteinsdottir, Unnur | Barroso, Inês | Fox, Caroline S | North, Kari E | Strachan, David P | Beckmann, Jacques S. | Berndt, Sonja I | Boehnke, Michael | Borecki, Ingrid B | McCarthy, Mark I | Metspalu, Andres | Stefansson, Kari | Uitterlinden, André G | van Duijn, Cornelia M | Franke, Lude | Willer, Cristen J | Price, Alkes L. | Lettre, Guillaume | Loos, Ruth JF | Weedon, Michael N | Ingelsson, Erik | O’Connell, Jeffrey R | Abecasis, Goncalo R | Chasman, Daniel I | Goddard, Michael E | Visscher, Peter M | Hirschhorn, Joel N | Frayling, Timothy M
Nature genetics  2014;46(11):1173-1186.
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explain one-fifth of heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ~2,000, ~3,700 and ~9,500 SNPs explained ~21%, ~24% and ~29% of phenotypic variance. Furthermore, all common variants together captured the majority (60%) of heritability. The 697 variants clustered in 423 loci enriched for genes, pathways, and tissue-types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin, and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
doi:10.1038/ng.3097
PMCID: PMC4250049  PMID: 25282103
12.  Agreement between TOAST and CCS ischemic stroke classification 
Neurology  2014;83(18):1653-1660.
Objective:
The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems.
Methods:
Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems.
Results:
The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58–0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69–0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54–0.58).
Conclusion:
Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.
doi:10.1212/WNL.0000000000000942
PMCID: PMC4223086  PMID: 25261504
13.  INCREASE IN SINGLE-TABLET REGIMEN USE AND ASSOCIATED IMPROVEMENTS IN ADHERENCE-RELATED OUTCOMES IN HIV-INFECTED WOMEN 
Introduction
The use of single-tablet ART regimens and its implications on adherence among HIV-infected women have not been well-described.
Methods
Participants were enrolled in the Women’s Interagency HIV Study (WIHS), a longitudinal study of HIV infection in U.S. women. We examined semiannual trends in single-tablet regimen use and ART adherence, defined as self-reported 95% adherence in the past 6 months, during 2006–2013. In a nested cohort study, we assessed the comparative effectiveness of a single-tablet versus a multiple-tablet regimen with respect to adherence, virologic suppression, quality of life, and AIDS-defining events, using propensity score matching to account for demographic, behavioral, and clinical confounders. We also examined these outcomes in a subset of women switching from a multiple- to single-tablet regimen, using a case-crossover design.
Results
15,523 person-visits, representing 1,727 women (53% black, 29% Hispanic, 25% IDU, median age 47), were included. Use of single-tablet regimens among ART users increased from 7% in 2006 to 27% in 2013; adherence increased from 78% to 85% during the same period (both p<0.001). Single-tablet regimen use was significantly associated with increased adherence (adjusted RR 1.05, 95% CI 1.03–1.08) and virologic suppression (RR 1.06, 95% CI 1.01–1.11), while associations with improved quality of life and fewer AIDS-defining events did not achieve statistical significance. Similar findings were observed among the subset of switchers.
Conclusion
Single-tablet regimen use was associated with increased adherence and virologic suppression. Despite this, 15% of women prescribed ART were still not optimally adherent; additional interventions are needed to maximize therapeutic benefits.
doi:10.1097/QAI.0000000000000082
PMCID: PMC3999284  PMID: 24326606
adherence; antiretroviral therapy; HIV; time factors; United States; viral load; women
14.  RYR3 gene variants in subclinical atherosclerosis among HIV-infected women in the Women’s Interagency HIV Study (WIHS) 
Atherosclerosis  2014;233(2):666-672.
Background
Single nucleotide polymorphisms (SNPs) in the Ryanodine receptor 3 (RYR3) gene are associated with common carotid intima media thickness (CCA cIMT) in HIV-infected men. We evaluated SNPs in the RYR3 gene among HIV-infected women participating in Women’s Interagency HIV Study (WIHS).
Methods
CCA cIMT was measured using B-mode ultrasound and the 838 SNPs in the RYR3 gene region were genotyped using the Illumina HumanOmni2.5-quad beadchip. The CCA cIMT genetic association was assessed using linear regression analyses among 1213 women and also separately among White (n=139), Black (n=720) and Hispanic (n=354) women after adjusting for confounders. A summary measure of pooled association was estimated using a meta-analytic approach by combining the effect estimates from the three races. Haploblocks were inferred using Gabriel’s method and haplotype association analyses were conducted among the three races separately.
Results
SNP rs62012610 was associated with CCA cIMT among the Hispanics (p=4.41× 10−5), rs11856930 among Whites (p=5.62× 10−4), and rs2572204 among Blacks (p=2.45× 10−3). Meta-analysis revealed several associations of SNPs in the same direction and of similar magnitude, particularly among Blacks and Hispanics. Additionally, several haplotypes within three haploblocks containing SNPs previously related with CCA cIMT were also associated in Whites and Hispanics.
Discussion
Consistent with previous research among HIV-infected men, SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex, and warrants future studies to better understand regional SNP function.
doi:10.1016/j.atherosclerosis.2014.01.035
PMCID: PMC3965606  PMID: 24561552
RYR3; single nucleotide polymorphisms; HIV infection; CCA; cIMT; subclinical atherosclerosis
15.  Echolucency of the Carotid Artery Intima‐Media Complex and Intima‐Media Thickness Have Different Cardiovascular Risk Factor Relationships: The Women's Interagency HIV Study 
Background
Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging.
Methods and Results
We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group.
Conclusions
Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.
doi:10.1161/JAHA.114.001405
PMCID: PMC4345869  PMID: 25699995
carotid arteries; epidemiology; immune system; risk factors; ultrasonics
16.  Development of an Online Library of Patient-Reported Outcome Measures in Gastroenterology: The GI-PRO Database 
OBJECTIVES
Because gastrointestinal (GI) illnesses can cause physical, emotional, and social distress, patient-reported outcomes (PROs) are used to guide clinical decision making, conduct research, and seek drug approval. It is important to develop a mechanism for identifying, categorizing, and evaluating the over 100 GI PROs that exist. Here we describe a new, National Institutes of Health (NIH)-supported, online PRO clearinghouse—the GI-PRO database.
METHODS
Using a protocol developed by the NIH Patient-Reported Outcome Measurement Information System (PROMIS®), we performed a systematic review to identify English-language GI PROs. We abstracted PRO items and developed an online searchable item database. We categorized symptoms into content “bins” to evaluate a framework for GI symptom reporting. Finally, we assigned a score for the methodological quality of each PRO represented in the published literature (0–20 range; higher indicates better).
RESULTS
We reviewed 15,697 titles (κ > 0.6 for title and abstract selection), from which we identified 126 PROs. Review of the PROs revealed eight GI symptom “bins”: (i) abdominal pain, (ii) bloat/gas, (iii) diarrhea, (iv) constipation, (v) bowel incontinence/soilage, (vi) heartburn/reflux, (vii) swallowing, and (viii) nausea/vomiting. In addition to these symptoms, the PROs covered four psychosocial domains: (i) behaviors, (ii) cognitions, (iii) emotions, and (iv) psychosocial impact. The quality scores were generally low (mean 8.88±4.19; 0 (min)−20 (max)). In addition, 51% did not include patient input in developing the PRO, and 41% provided no information on score interpretation.
CONCLUSIONS
GI PROs cover a wide range of biopsychosocial symptoms. Although plentiful, GI PROs are limited by low methodological quality. Our online PRO library (www.researchcore.org/gipro/) can help in selecting PROs for clinical and research purposes.
doi:10.1038/ajg.2013.401
PMCID: PMC4275098  PMID: 24343547
17.  Insulin, Insulin-like Growth Factor-I, Endogenous Estradiol, and Risk of Colorectal Cancer in Postmenopausal Women 
Cancer research  2008;68(1):329-337.
Obesity is a risk factor for colorectal cancer, and hyperinsulinemia, a common condition in obese patients, may underlie this relationship. Insulin, in addition to its metabolic effects, has promitotic and antiapoptotic activity that may be tumorigenic. Insulin-like growth factor (IGF)-I, a related hormone, shares sequence homology with insulin, and has even stronger mitogenic effects. However, few prospective colorectal cancer studies directly measured fasting insulin, and none evaluated free IGF-I, or endogenous estradiol, a potential cofactor in postmenopausal women. Therefore, we conducted a case-cohort investigation of colorectal cancer among nondiabetic subjects enrolled in the Women’s Health Initiative Observational Study, a prospective cohort of 93,676 postmenopausal women. Fasting baseline serum specimens from all incident colorectal cancer cases (n = 438) and a random subcohort (n = 816) of Women’s Health Initiative Observational Study subjects were tested for insulin, glucose, total IGF-I, free IGF-I, IGF binding protein-3, and estradiol. Comparing extreme quartiles, insulin [hazard ratio (HR)q4–q1, 1.73; 95% confidence interval (CI), 1.16–2.57; ptrend = 0.005], waist circumference (HRq4–q1, 1.82; 95% CI, 1.22–2.70; ptrend = 0.001), and free IGF-I (HRq4–q1, 1.35; 95% CI, 0.92–1.98; Ptrend = 0.05) were each associated with colorectal cancer incidence in multivariate models. However, these associations each became nonsignificant when adjusted for one another. Endogenous estradiol levels, in contrast, were positively associated with risk of colorectal cancer (HR comparing high versus low levels, 1.53; 95% CI, 1.05–2.22), even after control for insulin, free IGF-I, and waist circumference. These data suggest the existence of at least two independent biological pathways that are related to colorectal cancer: one that involves endogenous estradiol, and a second pathway broadly associated with obesity, hyperinsulinemia, and free IGF-I.
doi:10.1158/0008-5472.CAN-07-2946
PMCID: PMC4225702  PMID: 18172327
18.  Factors to Inform Clinicians About the End of Life in Severe Chronic Obstructive Pulmonary Disease 
Journal of pain and symptom management  2013;46(4):491-499.e4.
Context
Palliative services have historically been offered to terminal cancer patients, but much less so in other chronic illnesses like chronic obstructive pulmonary disease (COPD) because of difficulties in predicting the trajectory to death.
Objectives
The goal of this study was to determine if the change over time of key parameters (trajectory) in severe COPD patients can independently predict short-term mortality.
Methods
We analyzed data from 1218 patients with severe COPD. Multivariate models for trajectory change were used to forecast mortality at 12 months.
Results
Changes in several variables by defined cutpoints increase significantly and independently the odds of dying in 12 months. The earliest and strongest predictors were the decrease in gait speed by 0.14 m/sec or six-minute walk by 50m (OR 4.40, P<0.0001). Alternatively, if six-minute walk or gait speed were not used, change toward perceiving a very sedentary -state using single question- (OR 3.56, p=0.0007)and decrease in maximal inspiratory pressure >11 cm H2O (OR 2.19, p=0.0217). Then, and change toward feeling upset or downhearted (OR 2.44, p=0.0250), decrease in room air resting PaO2 >5 mmHg (OR 2.46, p=0.0156), increase in room air resting PaCO2 >3 mmHg (OR 2.8, p=0.0039). Change over time models were more discriminative (lower c-statistics) than change form baseline models.
Conclusion
The changes in defined variables and patient-reported outcomes by defined cutpoints were independently associated with increased 12-month mortality in patients with severe COPD. These results may inform clinicians when to initiate end-of-life communications and palliative care.
doi:10.1016/j.jpainsymman.2012.10.283
PMCID: PMC3728164  PMID: 23522520
Chronic obstructive pulmonary disease; severe COPD; end-stage COPD; palliative care; end-of-life care; gait speed; mortality; prediction tools
19.  The role of insulin-like growth factor-I and its binding proteins in glucose homeostasis and type 2 diabetes 
Summary
This review addresses the possible role of the insulin-like growth factor (IGF)-axis in normal glucose homoeostasis and in the etiopathogenesis of type 2 diabetes. IGF-I, a peptide hormone, shares amino acid sequence homology with insulin and has insulin-like activity; most notably, the promotion of glucose uptake by peripheral tissues. Type 2 diabetes as well as pre-diabetic states, including impaired fasting glucose and impaired glucose tolerance, are associated cross-sectionally with altered circulating levels of IGF-I and its binding proteins (IGFBPs). Administration of recombinant human IGF-I has been reported to improve insulin sensitivity in healthy individuals as well as in patients with insulin resistance and type 2 diabetes. Further, IGF-I may have beneficial effects on systemic inflammation, a risk factor for type 2 diabetes, and on pancreatic β-cell mass and function. There is considerable inter-individual heterogeneity in endogenous levels of IGF-I and its binding proteins; however, the relationship between these variations and the risk of developing type 2 diabetes has not been extensively investigated. Large prospective studies are required to evaluate this association.
doi:10.1002/dmrr.919
PMCID: PMC4153414  PMID: 19145587
insulin-like growth factor (IGF)-I; glucose; diabetes; IGFBP
21.  Measuring the Impact of Cataract Surgery on Generic and Vision-Specific Quality of Life 
Purpose
Cataracts are the leading cause of blindness worldwide and cause visual impairment for millions of adults in the US. We compared the sensitivity of a vision-specific health-related quality of life (HRQOL) measure to that of multiple generic measures of HRQOL before and at 2 two points after cataract surgery.
Methods
Participants completed 1 vision-specific and 5 generic quality of life measures before cataract surgery, and again 1-month, and 6-months after surgery. Random effects modeling was used to measure changes over the three assessment points.
Results
The NEI-VFQ25 total score and all 11 subscales showed significant improvements during the first interval (baseline and 1-month). During the second interval (1-month to 6-months post-surgery), significant improvements were observed on the total score and 5 of 11 NEI-VFQ25 subscales. There were significant increases in HRQOL during the first interval on some preference-based generic HRQOL measures, though changes during the second interval were mostly non-significant. None of the SF-36v2™ or SF6D scales changed significantly between any of the assessment periods.
Conclusions
The NEI-VFQ25 was sensitive to changes in vision-specific domains of QOL. Some preference-based generic HRQOL measures were also sensitive to change and showed convergence with the NEI-VFQ25, but the effects were small. The SF-36v2™ and SF-6D did not change in a similar manner, possibly reflecting a lack of vision-related content. Studies seeking to document both the vision-specific and generic HRQOL improvements of cataract surgery should consider these results when selecting measures.
doi:10.1007/s11136-012-0270-z
PMCID: PMC3578053  PMID: 23015266
22.  Resistin, but not Adiponectin and Leptin, is Associated with the Risk of Ischemic Stroke Among Postmenopausal Women: Results from the Women’s Health Initiative 
Background
Adipose tissue is considered an endocrine organ that secretes adipokines which possibly mediate the effects of obesity on risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and risk of ischemic stroke. We aimed to examine the associations of three adipokines (adiponectin, leptin and resistin) with risk of ischemic stroke.
Methods and Results
We conducted a prospective nested case-control study (972 stroke cases and 972 matched controls) within the Women’s Health Initiative Observational Study cohort. The controls were matched to cases on age, race/ethnicity, date of study enrollment and follow-up time. Adipokine levels were associated with established stroke risk factors, such as obesity and systolic blood pressure. Adjusted for body mass index, the odds ratios (OR) for incident ischemic stroke comparing the highest (Q4) to the lowest quartile (Q1) were 0.81 (95% confidence intervals [CI]: 0.61–1.08; p-trend: 0.068) for adiponectin, 1.15 (95% CI: 0.83–1.59; p-trend: 0.523) for leptin, and 1.57 (95% CI: 1.18–2.08; p-trend: 0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR: 1.39; 95% CI: 1.01–1.90; p-trend: 0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results.
Conclusions
Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other CVD risk factors.
doi:10.1161/STROKEAHA.110.607853
PMCID: PMC4059356  PMID: 21546486
stroke; adipokines; women
23.  A Robust Method for Genome-wide Association Meta-Analysis with the Application to Circulating Insulin-like Growth Factor I Concentrations 
Genetic epidemiology  2013;38(2):162-171.
Genome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This paper describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating Insulin-like growth factor I concentrations.
doi:10.1002/gepi.21766
PMCID: PMC4049273  PMID: 24446417
Genome-wide association study; Meta-analysis; Variance-component model; Insulin-like growth factor I
24.  Screening Mammography & Breast Cancer Mortality: Meta-Analysis of Quasi-Experimental Studies 
PLoS ONE  2014;9(6):e98105.
Background
The magnitude of the benefit associated with screening has been debated. We present a meta-analysis of quasi-experimental studies on the effects of mammography screening.
Methods
We searched MEDLINE/PubMed and Embase for articles published through January 31, 2013. Studies were included if they reported: 1) a population-wide breast cancer screening program using mammography with 5+ years of data post-implementation; 2) a comparison group with equal access to therapies; and 3) breast cancer mortality. Studies excluded were: RCTs, case-control, or simulation studies. We defined quasi-experimental as studies that compared either geographical, historical or birth cohorts with a screening program to an equivalent cohort without a screening program. Meta-analyses were conducted in Stata using the metan command, random effects. Meta-analyses were conducted separately for ages screened: under 50, 50 to 69 and over 70 and weighted by population and person-years.
Results
Among 4,903 published papers that were retrieved, 19 studies matched eligibility criteria. Birth cohort studies reported a significant benefit for women screened
Conclusions
Mammography screening may have modest effects on cancer mortality between the ages of 50 and 69 and non-significant effects for women older than age 70. Results are consistent with meta-analyses of RCTs. Effects on total mortality could not be assessed because of the limited number of studies.
doi:10.1371/journal.pone.0098105
PMCID: PMC4041743  PMID: 24887150
AIDS (London, England)  2013;27(9):1516-1519.
Summary
Among 127 HIV-infected women, the magnitude of HDLc increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in LDLc and inflammation were unrelated. In the same population, predicted risk of coronary heart disease based upon levels of standard clinical risk factors was similar before and after HAART treatment. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of CVD.
doi:10.1097/QAD.0b013e32835fd8a9
PMCID: PMC3909663  PMID: 23435295
lipids; HAART; HIV infection; inflammation

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