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1.  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
2.  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
3.  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
4.  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
6.  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
7.  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
8.  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
9.  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
Background and Purpose
Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women.
Methods
The Hormones and Biomarkers Predicting Stroke (HaBPS) Study is a case-control study of blood biomarkers assayed in 972 ischemic stroke cases and 972 controls, nested in the Women’s Health Initiative Observational Study of 93,676 postmenopausal women followed for an average of 8 years. We evaluated additive predictive value of two commercially available biomarkers: c-reactive protein (CRP) and Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) to determine if they added to risk prediction by the Framingham Stroke Risk Score (FSRS) or by traditional risk factors (TRF) which included lipids and other variables not included in the FSRS. As measures of additive predictive value, we used the c-statistic, Net Reclassification Improvement (NRI), category-less NRI, and Integrated Discrimination Improvement Index (IDI).
Results
Addition of CRP to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall NRI of 6.3%, (case NRI=3.9%, control NRI=2.4%) .In particular, hs-CRP was useful in prediction of cardioembolic strokes (NRI=12.0%; 95%CI: 4.3-19.6%) and in strokes occurring in less than 3 years (NRI=7.9%, 95%CI: 0.8-14.9%). Lp-PLA2 was useful in risk prediction of large artery strokes (NRI=19.8%, 95%CI: 7.4 -32.1%) and in early strokes (NRI=5.8%, 95%CI: 0.4-11.2%).
Conclusions
CRP and Lp-PLA2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk.
doi:10.1111/j.1747-4949.2012.00860.x
PMCID: PMC3556354  PMID: 23088183
Berndt, Sonja I. | Gustafsson, Stefan | Mägi, Reedik | Ganna, Andrea | Wheeler, Eleanor | Feitosa, Mary F. | Justice, Anne E. | Monda, Keri L. | Croteau-Chonka, Damien C. | Day, Felix R. | Esko, Tõnu | Fall, Tove | Ferreira, Teresa | Gentilini, Davide | Jackson, Anne U. | Luan, Jian’an | Randall, Joshua C. | Vedantam, Sailaja | Willer, Cristen J. | Winkler, Thomas W. | Wood, Andrew R. | Workalemahu, Tsegaselassie | Hu, Yi-Juan | Lee, Sang Hong | Liang, Liming | Lin, Dan-Yu | Min, Josine L. | Neale, Benjamin M. | Thorleifsson, Gudmar | Yang, Jian | Albrecht, Eva | Amin, Najaf | Bragg-Gresham, Jennifer L. | Cadby, Gemma | den Heijer, Martin | Eklund, Niina | Fischer, Krista | Goel, Anuj | Hottenga, Jouke-Jan | Huffman, Jennifer E. | Jarick, Ivonne | Johansson, Åsa | Johnson, Toby | Kanoni, Stavroula | Kleber, Marcus E. | König, Inke R. | Kristiansson, Kati | Kutalik, Zoltán | Lamina, Claudia | Lecoeur, Cecile | Li, Guo | Mangino, Massimo | McArdle, Wendy L. | Medina-Gomez, Carolina | Müller-Nurasyid, Martina | Ngwa, Julius S. | Nolte, Ilja M. | Paternoster, Lavinia | Pechlivanis, Sonali | Perola, Markus | Peters, Marjolein J. | Preuss, Michael | Rose, Lynda M. | Shi, Jianxin | Shungin, Dmitry | Smith, Albert Vernon | Strawbridge, Rona J. | Surakka, Ida | Teumer, Alexander | Trip, Mieke D. | Tyrer, Jonathan | Van Vliet-Ostaptchouk, Jana V. | Vandenput, Liesbeth | Waite, Lindsay L. | Zhao, Jing Hua | Absher, Devin | Asselbergs, Folkert W. | Atalay, Mustafa | Attwood, Antony P. | Balmforth, Anthony J. | Basart, Hanneke | Beilby, John | Bonnycastle, Lori L. | Brambilla, Paolo | Bruinenberg, Marcel | Campbell, Harry | Chasman, Daniel I. | Chines, Peter S. | Collins, Francis S. | Connell, John M. | Cookson, William | de Faire, Ulf | de Vegt, Femmie | Dei, Mariano | Dimitriou, Maria | Edkins, Sarah | Estrada, Karol | Evans, David M. | Farrall, Martin | Ferrario, Marco M. | Ferrières, Jean | Franke, Lude | Frau, Francesca | Gejman, Pablo V. | Grallert, Harald | Grönberg, Henrik | Gudnason, Vilmundur | Hall, Alistair S. | Hall, Per | Hartikainen, Anna-Liisa | Hayward, Caroline | Heard-Costa, Nancy L. | Heath, Andrew C. | Hebebrand, Johannes | Homuth, Georg | Hu, Frank B. | Hunt, Sarah E. | Hyppönen, Elina | Iribarren, Carlos | Jacobs, Kevin B. | Jansson, John-Olov | Jula, Antti | Kähönen, Mika | Kathiresan, Sekar | Kee, Frank | Khaw, Kay-Tee | Kivimaki, Mika | Koenig, Wolfgang | Kraja, Aldi T. | Kumari, Meena | Kuulasmaa, Kari | Kuusisto, Johanna | Laitinen, Jaana H. | Lakka, Timo A. | Langenberg, Claudia | Launer, Lenore J. | Lind, Lars | Lindström, Jaana | Liu, Jianjun | Liuzzi, Antonio | Lokki, Marja-Liisa | Lorentzon, Mattias | Madden, Pamela A. | Magnusson, Patrik K. | Manunta, Paolo | Marek, Diana | März, Winfried | Mateo Leach, Irene | McKnight, Barbara | Medland, Sarah E. | Mihailov, Evelin | Milani, Lili | Montgomery, Grant W. | Mooser, Vincent | Mühleisen, Thomas W. | Munroe, Patricia B. | Musk, Arthur W. | Narisu, Narisu | Navis, Gerjan | Nicholson, George | Nohr, Ellen A. | Ong, Ken K. | Oostra, Ben A. | Palmer, Colin N.A. | Palotie, Aarno | Peden, John F. | Pedersen, Nancy | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P. | Prokopenko, Inga | Pütter, Carolin | Radhakrishnan, Aparna | Raitakari, Olli | Rendon, Augusto | Rivadeneira, Fernando | Rudan, Igor | Saaristo, Timo E. | Sambrook, Jennifer G. | Sanders, Alan R. | Sanna, Serena | Saramies, Jouko | Schipf, Sabine | Schreiber, Stefan | Schunkert, Heribert | Shin, So-Youn | Signorini, Stefano | Sinisalo, Juha | Skrobek, Boris | Soranzo, Nicole | Stančáková, Alena | Stark, Klaus | Stephens, Jonathan C. | Stirrups, Kathleen | Stolk, Ronald P. | Stumvoll, Michael | Swift, Amy J. | Theodoraki, Eirini V. | Thorand, Barbara | Tregouet, David-Alexandre | Tremoli, Elena | Van der Klauw, Melanie M. | van Meurs, Joyce B.J. | Vermeulen, Sita H. | Viikari, Jorma | Virtamo, Jarmo | Vitart, Veronique | Waeber, Gérard | Wang, Zhaoming | Widén, Elisabeth | Wild, Sarah H. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Witteman, Jacqueline C.M. | Wolffenbuttel, Bruce H.R. | Wong, Andrew | Wright, Alan F. | Zillikens, M. Carola | Amouyel, Philippe | Boehm, Bernhard O. | Boerwinkle, Eric | Boomsma, Dorret I. | Caulfield, Mark J. | Chanock, Stephen J. | Cupples, L. Adrienne | Cusi, Daniele | Dedoussis, George V. | Erdmann, Jeanette | Eriksson, Johan G. | Franks, Paul W. | Froguel, Philippe | Gieger, Christian | Gyllensten, Ulf | Hamsten, Anders | Harris, Tamara B. | Hengstenberg, Christian | Hicks, Andrew A. | Hingorani, Aroon | Hinney, Anke | Hofman, Albert | Hovingh, Kees G. | Hveem, Kristian | Illig, Thomas | Jarvelin, Marjo-Riitta | Jöckel, Karl-Heinz | Keinanen-Kiukaanniemi, Sirkka M. | Kiemeney, Lambertus A. | Kuh, Diana | Laakso, Markku | Lehtimäki, Terho | Levinson, Douglas F. | Martin, Nicholas G. | Metspalu, Andres | Morris, Andrew D. | Nieminen, Markku S. | Njølstad, Inger | Ohlsson, Claes | Oldehinkel, Albertine J. | Ouwehand, Willem H. | Palmer, Lyle J. | Penninx, Brenda | Power, Chris | Province, Michael A. | Psaty, Bruce M. | Qi, Lu | Rauramaa, Rainer | Ridker, Paul M. | Ripatti, Samuli | Salomaa, Veikko | Samani, Nilesh J. | Snieder, Harold | Sørensen, Thorkild I.A. | Spector, Timothy D. | Stefansson, Kari | Tönjes, Anke | Tuomilehto, Jaakko | Uitterlinden, André G. | Uusitupa, Matti | van der Harst, Pim | Vollenweider, Peter | Wallaschofski, Henri | Wareham, Nicholas J. | Watkins, Hugh | Wichmann, H.-Erich | Wilson, James F. | Abecasis, Goncalo R. | Assimes, Themistocles L. | Barroso, Inês | Boehnke, Michael | Borecki, Ingrid B. | Deloukas, Panos | Fox, Caroline S. | Frayling, Timothy | Groop, Leif C. | Haritunian, Talin | Heid, Iris M. | Hunter, David | Kaplan, Robert C. | Karpe, Fredrik | Moffatt, Miriam | Mohlke, Karen L. | O’Connell, Jeffrey R. | Pawitan, Yudi | Schadt, Eric E. | Schlessinger, David | Steinthorsdottir, Valgerdur | Strachan, David P. | Thorsteinsdottir, Unnur | van Duijn, Cornelia M. | Visscher, Peter M. | Di Blasio, Anna Maria | Hirschhorn, Joel N. | Lindgren, Cecilia M. | Morris, Andrew P. | Meyre, David | Scherag, André | McCarthy, Mark I. | Speliotes, Elizabeth K. | North, Kari E. | Loos, Ruth J.F. | Ingelsson, Erik
Nature genetics  2013;45(5):501-512.
Approaches exploiting extremes of the trait distribution may reveal novel loci for common traits, but it is unknown whether such loci are generalizable to the general population. In a genome-wide search for loci associated with upper vs. lower 5th percentiles of body mass index, height and waist-hip ratio, as well as clinical classes of obesity including up to 263,407 European individuals, we identified four new loci (IGFBP4, H6PD, RSRC1, PPP2R2A) influencing height detected in the tails and seven new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3, ZZZ3) for clinical classes of obesity. Further, we show that there is large overlap in terms of genetic structure and distribution of variants between traits based on extremes and the general population and little etiologic heterogeneity between obesity subgroups.
doi:10.1038/ng.2606
PMCID: PMC3973018  PMID: 23563607
Journal of clinical epidemiology  2010;64(5):497-506.
OBJECTIVE
To compare the responsiveness to clinical change of 5 widely used preference-based health-related quality-of-life indexes in two longitudinal cohorts.
STUDY DESIGN AND SETTING
Five generic instruments were simultaneously administered to 376 adults undergoing cataract surgery, and 160 adults in heart failure management programs. Patients were assessed at baseline and reevaluated after 1 and 6 months. The measures were the SF-6D (based on responses scored from SF-36v2™), Self-Administered Quality of Well-being scale (QWB-SA), the EQ-5D developed by the EuroQoL Group, the Health Utilities Indexes Mark 2 (HUI2) and Mark 3 (HUI3). Cataract patients completed the National Eye Institute Visual Functioning Questionnaire (VFQ-25) and heart failure patients completed the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Responsiveness was estimated by the Standardized Response Mean (SRM).
RESULTS
For cataract patients, mean changes between baseline and 1 month follow-up for the generic indices ranged from 0.00 (SF-6D) to 0.052 (HUI3) and were statistically significant for all indexes except the SF-6D. For heart failure patients, only the SF-6D showed significant change from baseline to 1 month, while only the QWB-SA change was significant between 1 and 6 months.
CONCLUSIONS
Preference-based methods for measuring health outcomes are not equally responsive to change.
doi:10.1016/j.jclinepi.2010.04.010
PMCID: PMC3973151  PMID: 20685077
Quality of Life; Measurement; Responsiveness; Cost-Utility Analysis
Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. HIV infection and treatment are associated with hypercoaguability; thrombosis in HCV is under-investigated. Proposed markers of hemostasis in HIV include higher D-dimer, Factor VIII% and Plasminogen Activator Inhibitor-1 (PAI-1Ag), and lower total Protein S% (TPS), but have not been examined in HCV. We assessed the independent association of HCV with these four measures of hemostasis in a multicenter, prospective study of HIV: the Women’s Interagency HIV Study (WIHS).
We randomly selected 450 HCV-infected (anti-HCV+ with detectable plasma HCV RNA) and 450 HCV-uninfected (anti-HCV−) women. HCV was the main exposure of interest in regression models.
443 HCV+ and 425 HCV− women were included. HCV+ women had higher Factor VIII% (124.4% ±3.9 vs. 101.8% ±3.7, p <0.001) and lower TPS (75.7% ±1.1 vs. 84.3% ±1.1, <0.001) than HCV−, independent of HIV infection and viral load; there was little difference in PAI-1Ag or log10 D-dimer. After adjustment for confounders, these inferences remained. HIV infection was independently associated with higher Factor VIII% and log10 D-dimer, and lower TPS.
HCV was independently associated with higher Factor VIII% and lower TPS consistent with hypercoaguability. Higher Factor VIII % and D-dimer and lower total Protein S % were also strongly associated with HIV infection and levels of HIV viremia, independent of HCV infection. Further investigation is needed to determine if there is increased thrombotic risk from HCV. Studies examining hemostasis markers in HIV infection must also assess the contribution of HCV infection.
doi:10.1097/QAI.0b013e31827fdd61
PMCID: PMC3652915  PMID: 23221984
Health Services Research  2012;47(1 Pt 2):431-445.
Objective
To test the hypotheses that reported asthma prevalence is higher among insured than uninsured children and that insurance-based differences in asthma diagnosis, treatment, and health care utilization are associated with disease severity.
Data Sources
National Health and Nutrition Examination Survey, 2003–2008.
Study Design
We used multivariate logistic regression to examine the relationship between insurance and asthma symptom severity with asthma diagnosis, treatment, and acute care utilization.
Principal Findings
In multivariate analysis, insured children had greater odds of reporting a current diagnosis of asthma than uninsured children (odds ratio [OR] = 2.08, 95% confidence interval [CI]: 1.47–2.94). When interactions between insurance and asthma impairment were included, insurance was associated with greater odds of diagnosis among children with intermittent (OR = 4.08, 95% CI: 1.57–10.61), but not persistent, symptoms. Among children with intermittent symptoms, insurance was associated with inhaled corticosteroid use (OR = 4.51, 95% CI: 1.18–17.24) and asthma-related acute care utilization (OR = 5.21, 95% CI: 1.21–23.53); these associations were nonsignificant among children with persistent symptoms.
Conclusion
Being insured increases only the likelihood that a child with intermittent, not persistent, asthma symptoms will receive an asthma diagnosis and control medication, and it may not reduce acute care utilization. Although universal insurance may increase detection and management of undiagnosed childhood asthma, theorized cost savings from reduced acute care utilization might not materialize.
doi:10.1111/j.1475-6773.2011.01339.x
PMCID: PMC3258307  PMID: 22091849
Asthma; children; insurance; asthma impairment; health services utilization
Health Services Research  2012;47(1 Pt 2):544-555.
Objective
To explore state patterns in the racial life expectancy gap.
Data Sources
The 1997–2004 Multiple Cause of Death PUF, 2000 U.S. Census.
Study Design
We calculated life expectancy at birth for black and white men and women.
Data Extraction Methods
Data were obtained by the NCHS and U.S. Census Bureau.
Principal Findings
States with small racial differences are due to higher-than-expected life expectancy for blacks or lower-than-expected for whites. States with large disparity are explained by higher-than-average life expectancy among whites or lower-than-average life expectancy among blacks.
Conclusions
Heterogeneous state patterns in racial disparity in life expectancy exist. Eliminating disparity in states with large black populations would make the greatest impact nationally.
doi:10.1111/j.1475-6773.2011.01345.x
PMCID: PMC3393007  PMID: 22092060
Life expectancy; disparity; black; United States
Background
Hepatocyte growth factor (HGF) is a potent angiogenic factor and may play a role in the development and progression of atherosclerotic lesions, the underlying mechanism of cardiovascular disease. However, there have been no prospective studies examining the relationship between HGF levels and risk of stroke.
Methods and Results
We conducted a nested case-control study (972 incident stroke cases and 1:1 age- and race-matched controls) to prospectively evaluate the association between plasma HGF and risk of ischemic stroke within the Women’s Health Initiative Observational Study, a cohort of postmenopausal women aged 50–79 years. Baseline HGF levels were correlated positively with body mass index (BMI), systolic blood pressure, low-density lipoprotein cholesterol, insulin resistance, and inflammatory markers such as C-reactive protein, and inversely with high-density lipoprotein cholesterol (all P-values <0.05). Baseline HGF levels were higher among cases than controls (geometric means 601.8 vs. 523.2 pg/mL, p = 0.003). Furthermore, the risk of incident ischemic stroke was significantly greater amongst women in the highest versus lowest quartile of plasma HGF levels (odds ratio [OR] = 1.46; 95% confidence interval [CI]: 1.12–1.91; Ptrend = 0.003), in a conditional logistic regression model that adjusted for BMI. These results were only slightly attenuated after further adjustment for additional stroke risk factors (OR=1.39; 95% CI=1.04–1.85, Ptrend=0.023).
Conclusions
Circulating levels of HGF are associated with an increased risk of incident ischemic stroke, independent of obesity and other risk factors for cardiovascular disease among postmenopausal women aged 50–79 years.
doi:10.1161/STROKEAHA.109.567719
PMCID: PMC3903044  PMID: 20203323
Hepatocyte growth factor; ischemic stroke; women
Circulation. Heart failure  2013;6(3):364-370.
Background
Patients with heart failure (HF) have higher fasting insulin levels and a higher prevalence of insulin resistance (IR) as compared with matched controls. IR leads to structural abnormalities in the heart, such as increased left atrial (LA) size, left ventricular (LV) mass, and alterations in transmitral velocity that can precede the diagnosis of HF. It is not known whether IR precedes the development of HF or whether the relationship between IR and HF is present among adults with HF due to non-ischemic heart disease.
Methods and Results
We examined 4425 participants (60% female) from the Cardiovascular Health Study after excluding those with HF, myocardial infarction, or treated diabetes at baseline. We used Cox proportional hazards models to estimate the relative risk of incident HF associated with fasting insulin measured at study entry.
There were 1216 cases of incident HF (1103 without antecedent MI) during a median follow-up of 12 years (maximum, 19 years). Fasting insulin levels were positively associated with the risk of incident HF (HR = 1.10, 95% CI 1.05, 1.15, per SD change) when adjusted for age, gender, race, field center, physical activity, smoking, alcohol intake, HDL cholesterol, total cholesterol, and systolic blood pressure, and waist circumference. The association between fasting insulin levels and incident HF was similar for HF without antecedent MI (HR= 1.10, 95% CI 1.05, 1.15). Measures of LA size, LV mass, and peak A velocity at baseline were associated both with fasting insulin levels and with heart failure ; however, additional statistical adjustment for these parameters did not completely attenuate the insulin-HF estimate (HR= 1.08, 95% CI 1.03, 1.14 per1-SD increase in fasting insulin).
Conclusion
Fasting insulin was positively associated with adverse echocardiographic features and risk of subsequent HF in CHS participants, including those without an antecedent MI.
doi:10.1161/CIRCHEARTFAILURE.112.000022
PMCID: PMC3888807  PMID: 23575256
heart failure; insulin; epidemiology
Atherosclerosis  2012;225(2):408-411.
Objective
We examined serum lipids in association with carotid artery intima-media thickness (CIMT) in HIV-infected and HIV-uninfected women.
Methods
In 2003–4, among 1827 Women’s Interagency HIV Study participants, we measured CIMT and lipids (high-density lipoprotein cholesterol [HDL-c], low-density lipoprotein cholesterol [LDL-c], total cholesterol [TC], non-HDL-c). A subset of 520 treated HIV-infected women had pre-1997 lipid measures. We used multivariable linear regression to examine associations between lipids and CIMT.
Results
In HIV-uninfected women, higher TC, LDL-c and non-HDL-c were associated with increased CIMT. Among HIV-infected women, associations of lipids with CIMT were observed in treated but not untreated women. Among the HIV-infected women treated in 2003–4, CIMT was associated both with lipids measured a decade earlier in infection, and with late lipid measurements.
Conclusion
Among HIV-infected women, hyperlipidemia is most strongly associated with subclinical atherosclerosis in treated women. Among treated women, the association appeared strongest early in the disease course.
doi:10.1016/j.atherosclerosis.2012.09.035
PMCID: PMC3696584  PMID: 23089369
cardiovascular diseases; carotid arteries; HAART; HIV; lipids
Diabetes Care  2012;35(11):2226-2234.
OBJECTIVE
To examine determinants of racial/ethnic differences in diabetes incidence among postmenopausal women participating in the Women’s Health Initiative.
RESEARCH DESIGN AND METHODS
Data on race/ethnicity, baseline diabetes prevalence, and incident diabetes were obtained from 158,833 women recruited from 1993–1998 and followed through August 2009. The relationship between race/ethnicity, other potential risk factors, and the risk of incident diabetes was estimated using Cox proportional hazards models from which hazard ratios (HRs) and 95% CIs were computed.
RESULTS
Participants were aged 63 years on average at baseline. The racial/ethnic distribution was 84.1% non-Hispanic white, 9.2% non-Hispanic black, 4.1% Hispanic, and 2.6% Asian. After an average of 10.4 years of follow-up, compared with whites and adjusting for potential confounders, the HRs for incident diabetes were 1.55 for blacks (95% CI 1.47–1.63), 1.67 for Hispanics (1.54–1.81), and 1.86 for Asians (1.68–2.06). Whites, blacks, and Hispanics with all factors (i.e., weight, physical activity, dietary quality, and smoking) in the low-risk category had 60, 69, and 63% lower risk for incident diabetes. Although contributions of different risk factors varied slightly by race/ethnicity, most findings were similar across groups, and women who had both a healthy weight and were in the highest tertile of physical activity had less than one-third the risk of diabetes compared with obese and inactive women.
CONCLUSIONS
Despite large racial/ethnic differences in diabetes incidence, most variability could be attributed to lifestyle factors. Our findings show that the majority of diabetes cases are preventable, and risk reduction strategies can be effectively applied to all racial/ethnic groups.
doi:10.2337/dc12-0412
PMCID: PMC3476929  PMID: 22833490
Cancer research  2012;72(12):3029-3037.
Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case–cohort study nested within the Women’s Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines—adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of antiinflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HRQ4–Q1), 1.84; 95% CI, 1.17–2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.
doi:10.1158/0008-5472.CAN-11-2771
PMCID: PMC3790260  PMID: 22511581
Science (New York, N.Y.)  2013;339(6126):1390-1392.
Developments in geographic science and technology can increase our understanding of disease prevalence, etiology, transmission, and treatment.
doi:10.1126/science.1232257
PMCID: PMC3757548  PMID: 23520099
Context
Major cardiovascular diseases (CVDs) are leading causes of mortality among US Hispanic and Latino individuals. Comprehensive data are limited regarding the prevalence of CVD risk factors in this population and relations of these traits to socioeconomic status (SES) and acculturation.
Objectives
To describe prevalence of major CVD risk factors and CVD (coronary heart disease [CHD] and stroke) among US Hispanic/Latino individuals of different backgrounds, examine relationships of SES and acculturation with CVD risk profiles and CVD, and assess cross-sectional associations of CVD risk factors with CVD.
Design, Setting, and Participants
Multicenter, prospective, population-based Hispanic Community Health Study/Study of Latinos including individuals of Cuban (n =2201), Dominican (n = 1400), Mexican (n=6232), Puerto Rican (n=2590), Central American (n=1634), and South American backgrounds (n = 1022) aged 18 to 74 years. Analyses involved 15 079 participants with complete data enrolled between March 2008 and June 2011.
Main Outcome Measures
Adverse CVD risk factors defined using national guidelines for hypercholesterolemia, hypertension, obesity, diabetes, and smoking. Prevalence of CHD and stroke were ascertained from self-reported data.
Results
Age-standardized prevalence of CVD risk factors varied by Hispanic/Latino background; obesity and current smoking rates were highest among Puerto Rican participants (for men, 40.9% and 34.7%; for women, 51.4% and 31.7%, respectively); hypercholesterolemia prevalence was highest among Central American men (54.9%) and Puerto Rican women (41.0%). Large proportions of participants (80% of men, 71% of women) had at least 1 risk factor. Age- and sex-adjusted prevalence of 3 or more risk factors was highest in Puerto Rican participants (25.0%) and significantly higher (P<.001) among participants with less education (16.1%), those who were US-born (18.5%), those who had lived in the United States 10 years or longer (15.7%), and those who preferred English (17.9%). Overall, self-reported CHD and stroke prevalence were low (4.2% and 2.0% in men; 2.4% and 1.2% in women, respectively). In multivariate-adjusted models, hypertension and smoking were directly associated with CHD in both sexes as were hypercholesterolemia and obesity in women and diabetes in men (odds ratios [ORs], 1.5–2.2). For stroke, associations were positive with hypertension in both sexes, diabetes in men, and smoking in women (ORs, 1.7–2.6).
Conclusion
Among US Hispanic/Latino adults of diverse backgrounds, a sizeable proportion of men and women had adverse major risk factors; prevalence of adverse CVD risk profiles was higher among participants with Puerto Rican background, lower SES, and higher levels of acculturation.
doi:10.1001/jama.2012.14517
PMCID: PMC3777250  PMID: 23117778
Diabetes  2012;61(9):2248-2254.
IGF-I shares structural homology and in vitro metabolic activity with insulin. Laboratory models suggest that IGF-I and its binding proteins IGFBP-1 and IGFBP-2 have potentially beneficial effects on diabetes risk, whereas IGFBP-3 may have adverse effects. We therefore conducted a prospective nested case-control investigation of incident diabetes (n = 742 case subjects matched 1:1 to control subjects) and its associations with IGF-axis protein levels in the Nurses’ Health Study, a cohort of middle-aged women. The median time to diabetes was 9 years. Statistical analyses were adjusted for multiple risk factors, including insulin and C-reactive protein. Diabetes risk was fivefold lower among women with baseline IGFBP-2 levels in the top versus bottom quintile (odds ratio [OR]q5–q1 = 0.17 [95% CI 0.08–0.35]; P trend < 0.0001) and was also negatively associated with IGFBP-1 levels (ORq5–q1 = 0.37 [0.18–0.73]; P trend = 0.0009). IGFBP-3 was positively associated with diabetes (ORq5–q1 = 2.05 [1.20–3.51]; P trend = 0.002). Diabetes was not associated with total IGF-I levels, but free IGF-I and diabetes had a significant association that varied (P interaction = 0.003) by insulin levels above the median (ORq5–q1 = 0.48 [0.26–0.90]; P trend = 0.0001) versus below the median (ORq5–q1 = 2.52 [1.05–6.06]; P trend < 0.05). Thus, this prospective study found strong associations of incident diabetes with baseline levels of three IGFBPs and free IGF-I, consistent with hypotheses that the IGF axis might influence diabetes risk.
doi:10.2337/db11-1488
PMCID: PMC3425426  PMID: 22554827
Background
Preference-based measures of health-related quality of life all use the same dead = 0.00 to perfect health = 1.00 scale, but there are substantial differences among measures.
Objective
The objective is to examine agreement in classifying patients as better, stable, or worse.
Design
The EQ-5D, Health Utilities Index Mark 2 and Mark 3, Quality of Well-Being – Self-Administered, Short-Form 36 (Short-Form 6D), and disease-targeted measures were administered prospectively in two clinical cohorts.
Setting
The study was conducted at academic medical centers: University of California, Los Angeles; University of California, San Diego; University of Wisconsin-Madison; and University of Southern California.
Patients
Patients undergoing cataract extraction surgery with lens replacement completed the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25). Patients newly refereed to congestive heart failure specialty clinics completed the Minnesota Living with Heart Failure Questionnaire (MLHF).
Measurements
In both cohorts subjects completed surveys at baseline, one and six months. The NEI-VFQ-25 and MLHF were used as gold standards to assign patients to categories of change. Agreement was assessed using kappa.
Results
376 cataract patients were recruited. Complete data for baseline and the one-month follow-up were available on all measures for 210 cases. Using criteria specified by Altman, agreement was poor for six of nine pairs of comparisons and fair for three pairs. 160 heart failure patients were recruited. Complete data for baseline and the six-month follow-up were available for 86 cases. Agreement was negligible for five pairs and fair for one.
Limitations
The study was conducted on selected patients at a few academic medical centers.
Conclusions
The results underscore the lack of interchangeability among different preference-based measures.
doi:10.1177/0272989X11418671
PMCID: PMC3749910  PMID: 22009666

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