Publications by authors named "Amy Barrett"

58 Publications

Use of Patient and Investigator Global Impression Scales: A Review of Food and Drug Administration-Approved Labeling, 2009 to 2019.

Value Health 2021 07 1;24(7):1016-1023. Epub 2021 Apr 1.

RTI Health Solutions, Research Triangle Park, NC, USA.

Objective: Identify disease categories in which single-item global impression (GI) scales were included in product labeling of new drugs approved by the US Food and Drug Administration (FDA) in January 2009-December 2019 and review the characteristics of GIs included in product labeling of new FDA-approved drugs (January 2017-December 2019).

Methods: FDA Clinical Outcome Assessment (COA) Compendium was reviewed for drug labels that included GIs for drugs approved in 2009-2016. The indication, year of approval, ICD-10 code, and GI respondent were noted. A manual review of labels of FDA-approved drugs (2017-2019) was undertaken to identify GIs included in the labels. Corresponding drug approval packages were reviewed to identify details of any regulatory reviewer comments related to GIs. GI characteristics were noted from the drug label or the review documents, including the respondent, type of measure (static or dynamic), item wording, concept assessed, and response options.

Results: Product labeling containing GIs was most common in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs were included in 30/77 (39.0%) drug labels in the four disease categories.

Conclusion: In the past 10 years, GIs have been included as endpoint measures in confirmatory clinical trials and have generated evidence of treatment benefit in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs frequently provide important insights into the patient experience. Before GIs are included in clinical trials to assess treatment benefit, it is important to ensure that they are valid, reliable, and responsive.
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http://dx.doi.org/10.1016/j.jval.2021.01.005DOI Listing
July 2021

Quality of life, gastrointestinal symptoms, sleep problems, social support, and social functioning in adults with autism spectrum disorder.

Res Dev Disabil 2021 May 4;112:103915. Epub 2021 Mar 4.

Irish Centre for Autism and Neurodevelopmental Research (ICAN), School of Psychology, National University of Ireland, Galway, Ireland.

Background: The purpose of this study was to investigate the relationship between sleep problems, gastrointestinal symptoms, social functioning, autism traits, and social support on quality of life (QoL) in 107 adults with autism spectrum disorder (ASD).

Method: Questionnaires included the Autism Spectrum Quotient-10 (Adult), Multidimensional Scale of Perceived Social Support, Social Functioning Questionnaire, Pittsburgh Sleep Quality Index, Gastrointestinal Symptom Inventory, and World Health Organization Quality of Life-BREF.

Results: GI symptoms were a common comorbidity with 86 % of participants presenting with them. Sleep problems were also frequent issues with 89 % of participants being classified as poor sleepers. Greater sleep problems were correlated with poorer QoL in the physical health and environment domains. Specifically, the sleep problem of daytime dysfunction was correlated with poorer QoL in physical health. Daytime dysfunction and sleep duration were correlated with poorer QoL in the environment domain. Better social support was correlated with greater QoL in the psychological, social and environment domains. Poorer social functioning was correlated with poorer QoL in each of the four domains.

Conclusion: This research indicated that GI symptoms and sleep problems are common comorbid conditions in the adult ASD population. This paper expanded upon the existing literature by highlighting unexplored factors influencing QoL in adults with ASD.
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http://dx.doi.org/10.1016/j.ridd.2021.103915DOI Listing
May 2021

Oxidation of dietary linoleate occurs to a greater extent than dietary palmitate in vivo in humans.

Clin Nutr 2021 03 22;40(3):1108-1114. Epub 2020 Jul 22.

Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK. Electronic address:

Background: It has been suggested that dietary polyunsaturated fatty acids (PUFA) are partitioned into oxidation pathways to a greater extent than dietary saturated fatty acids (SFA). Whilst this has been demonstrated in animal models, evidence in humans is lacking. The potential divergence in the metabolic fate of these dietary fatty acids (FA) may explain some of the reported differences in ectopic fat deposition with SFA and PUFA enriched diets.

Aims: To compare whole-body oxidation of dietary palmitate and linoleate after consumption of a single test meal.

Methods: In a randomized, crossover design 24 healthy volunteers (12 males and 12 females, matched for age and BMI) underwent two study days separated by 2-week washout period. During each study day participants consumed a standardized test meal which contained [UC]palmitate or [UC]linoleate. Blood and breath samples were collected over the 6 h postprandial period and the C enrichment in breath CO samples and plasma lipid fractions was determined.

Results: Appearance of C in expired CO was significantly (p < 0.05) increased after consumption of the meal containing [UC]linoleate compared to the meal containing [UC]palmitate. The recovery of tracer was 8.9 ± 1.2% [UC]linoleate vs. 5.6 ± 0.4% [UC]palmitate (p < 0.05). The incorporation of C from [UC]palmitate was greater in plasma triacylglycerol and non-esterified fatty acids than [UC]linoleate, whereas the incorporation of C from [UC]linoleate was greater than [UC]palmitate in plasma phospholipids. Although CO was significantly (p < 0.05) higher in females compared to males after consumption of [UC]palmitate, there was no difference in CO between sexes after consumption of [UC]linoleate.

Conclusions: We demonstrate that whole-body oxidation of dietary linoleate is comparatively higher than that of dietary palmitate in humans following consumption of a single mixed-test meal. We found indications of sexual dimorphism for dietary palmitate but not dietary linoleate.

Study Registration: http://www.clinicaltrials.org/ ID number NCT03587753.
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http://dx.doi.org/10.1016/j.clnu.2020.07.013DOI Listing
March 2021

Increased Ephrin-B2 expression in pericytes contributes to retinal vascular death in rodents.

Vascul Pharmacol 2020 08 22;131:106761. Epub 2020 Jun 22.

Department of Biomedical Sciences, School of Medicine, Mercer University, Savannah, GA, USA. Electronic address:

Aims: Diabetes-induced retinal vascular cell death aggravates diabetic retinopathy (DR) to the proliferative stage and blindness. Pericytes play a crucial role in retinal capillaries survival, stability, and angiogenesis. Ephrin-B2 is a tyrosine kinase that regulates pericytes/endothelial cells communication during angiogenesis; yet, its role in DR is still unclear. We hypothesize that diabetes increases Ephrin-B2 signaling in pericytes, which contributes to inflammation and retinal vascular cell death.

Methods: Selective inhibition of the Ephrin-B2 expression in the retinal pericytes was achieved using an intraocular injection of adeno-associated virus (AAV) with a specific pericyte promotor. Vascular death was determined by retinal trypsin digest. Pathological angiogenesis was assessed using the oxygen-induced retinopathy model in pericyte-Ephrin-B2 knockout mice, wild type, and wild type injected with AAV. Angiogenic properties, inflammatory, and apoptotic markers were measured in human retinal pericytes (HRP) grown under diabetic conditions.

Key Finding: Diabetes significantly increased the expression of Ephrin-B2, inflammatory, and apoptotic markers in the diabetic retinas and HRP. These effects were prevented by silencing Ephrin-B2 in HRP. Moreover, Ephrin-B2 silencing in retinal pericytes decreased pathological angiogenesis and acellular capillaries formation in diabetic retinas.

Significance: Increased Ephrin-B2 expression in the pericytes contributed to diabetes-induced retinal inflammation and vascular death. These results identify pericytes-Ephrin-B2 as a therapeutic target for DR.
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http://dx.doi.org/10.1016/j.vph.2020.106761DOI Listing
August 2020

Effect of a Virtual Patient Navigation Program on Behavioral Health Admissions in the Emergency Department: A Randomized Clinical Trial.

JAMA Netw Open 2020 Jan 3;3(1):e1919954. Epub 2020 Jan 3.

Department of Psychiatry, Atrium Health, Charlotte, North Carolina.

Importance: The number of patients presenting to emergency departments (EDs) for psychiatric care continues to increase. Psychiatrists often make a conservative recommendation to admit patients because robust outpatient services for close follow-up are lacking.

Objective: To assess whether the availability of a 45-day behavioral health-virtual patient navigation program decreases hospitalization among patients presenting to the ED with a behavioral health crisis or need.

Design, Setting, And Participants: This randomized clinical trial enrolled 637 patients who presented to 6 EDs spanning urban and suburban locations within a large integrated health care system in North Carolina from June 12, 2017, through February 14, 2018; patients were followed up for up to 45 days. Eligible patients were aged 18 years or older, with a behavioral health crisis and a completed telepsychiatric ED consultation. The availability of the behavioral health-virtual patient navigation intervention was randomly allocated to specific days (Monday through Friday from 7 am to 7 pm) so that, in a 2-week block, there were 5 intervention days and 5 usual care days; 323 patients presented on days when the program was offered, and 314 presented on usual care days. Data analysis was performed from March 7 through June 13, 2018, using an intention-to-treat approach.

Interventions: The behavioral health-virtual patient navigation program included video contact with a patient while in the ED and telephonic outreach 24 to 72 hours after discharge and then at least weekly for up to 45 days.

Main Outcomes And Measures: The primary outcome was the conversion of an ED encounter to hospital admission. Secondary outcomes included 45-day follow-up encounters with a self-harm diagnosis and postdischarge acute care use.

Results: Among 637 participants, 358 (56.2%) were men, and the mean (SD) age was 39.7 (16.6) years. The conversion rates were 55.1% (178 of 323) in the intervention group vs 63.1% (198 of 314) in the usual care group (odds ratio, 0.74; 95% CI, 0.54-1.02; P = .06). The percentage of patient encounters with follow-up encounters having a self-harm diagnosis was significantly lower in the intervention group compared with the usual care group (36.8% [119 of 323] vs 45.5% [143 of 314]; P = .03).

Conclusions And Relevance: Although the primary result did not reach statistical significance, there is a strong signal of potential positive benefit in an area that lacks evidence, suggesting that there should be additional investment and inquiry into virtual behavioral health programs.

Trial Registration: ClinicalTrials.gov identifier: NCT03204643.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.19954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991284PMC
January 2020

Patient-Reported Outcome Measures in Atopic Dermatitis and Chronic Hand Eczema in Adults.

Patient 2019 10;12(5):445-459

RTI Health Solutions, 3040 Cornwallis Drive, PO Box 12194, Research Triangle Park, NC, 27709, USA.

Patient-reported outcome measures (PROMs) provide an important complement to physician-assessed clinical outcome measures in dermatologic diseases such as atopic dermatitis (AD) and chronic hand eczema (CHE). AD and CHE are chronic and relapsing inflammatory skin conditions that often co-occur. While both diseases result in various signs and symptoms that are burdensome and can negatively affect patients' lives, there may be distinct differences in the signs, symptoms, burden, and health-related quality of life (HRQOL) impact of these diseases. The objective of this study was to identify and evaluate PROMs used in studies of AD and CHE. The aim was to explore the assessment of key symptoms and impacts, and identify any gaps in the measures in use. A structured review of the PubMed database was conducted to identify PROMs used or developed for use in AD or CHE. The Dermatology Life Quality Index (DLQI), the Pruritus/Itch Numeric Rating Scale (NRS), the Patient-Oriented Eczema Measure (POEM), and the Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were identified and reviewed in detail. With these measures, the AD and CHE symptoms and impacts most commonly evaluated in the literature include dermatology-related HRQOL in the domains of symptoms and feelings, daily activities, leisure, work and school, personal relationships, and adverse effects; pruritus; sleep disturbance; AD-specific symptoms (dryness, itching, flaking, cracking, bleeding, and weeping/oozing); and CHE-specific symptoms (pain, itch, fissuring, redness, bleeding, and dryness). A review of regulatory labels of drugs approved for AD by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) found that, among the four measures reviewed, the Pruritus NRS was included in the FDA and EMA labels for dupilumab, the DLQI was included in the EMA labels for dupilumab and tacrolimus, and the POEM was included in the EMA label for dupilumab. Key symptoms of AD (e.g. itching, flaking, cracking) and CHE (e.g. pain, itching, fissuring) are increasingly being assessed with PROMs; however, primary endpoints in clinical trials are often based on clinician-reported outcome measures. As therapeutic strategies in dermatology are targeted at specific dermatologic symptoms and diseases affecting specific sites (e.g. CHE), future research should explore patients' experiences with these symptoms and sites and the changes with treatment that are most meaningful to them.
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http://dx.doi.org/10.1007/s40271-019-00373-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697713PMC
October 2019

Development of the Nocturia Sleep Quality Scale: a patient-reported outcome measure of sleep impact related to nocturia.

Sleep Med 2019 07 18;59:101-106. Epub 2019 Feb 18.

Henry Ford Hospital, Detroit, MI, USA. Electronic address:

Background/objective: Nocturia's impact on sleep causes significant burden for patients. This study aimed to develop a novel patient-reported outcome (PRO) measure, the Nocturia Sleep Quality Scale (NSQS), for the assessment of the impact of nocturia (defined as ≥2 nocturnal voids/night) on sleep.

Methods: Sleep-related concepts were identified through a targeted literature review, after which in-depth concept elicitation interviews with patients with a clinical diagnosis of nocturia were conducted. Draft items were generated to address concepts identified as important, meaningful, and relevant. Items were further refined through three iterative sets of cognitive debriefing interviews to optimize instructions, question wording, and response options. Two sleep research experts also provided input.

Results: The literature review and data from 18 concept elicitation interviews provided the basis for a comprehensive set of concepts. Constant comparative analysis was used to identify themes and support item development. The draft questionnaire consisted of 14 items with item-specific response scales. Wording and scaling of the items was optimized based on feedback from the 22 cognitive debriefing interviews and expert input. The results confirmed the completeness and relevance of the NSQS, providing support for the content validity and ability of items to reflect patient perception of nocturia-related sleep impacts.

Conclusions: The 6-item NSQS assesses the impact of nocturia on sleep by evaluating nighttime awakenings, sleep quantity, and sleep quality. The NSQS is self-administered and is intended to assess change in nocturia's impact on sleep after treatment in a standardized manner. Psychometric evaluation is under way to describe key measurement properties.
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http://dx.doi.org/10.1016/j.sleep.2019.02.006DOI Listing
July 2019

Development, psychometric evaluation, and initial feasibility assessment of a symptom tracker for use by patients with heart failure (HFaST).

J Patient Rep Outcomes 2019 May 2;3(1):26. Epub 2019 May 2.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Background: This study aimed to develop and provide a psychometric and feasibility pilot evaluation of the Heart Failure (HF) Symptom Tracker (HFaST), a new patient-reported tool designed to facilitate communication between patients and health care providers (HCPs) in routine clinical care. The HFaST enables patients to identify worsening HF symptoms, with a long-term goal of preventing hospitalizations or emergency room visits.

Methods: The HFaST was developed drawing on evidence from the literature, qualitatively with cognitive interviews (12 patient/caregiver and 8 HCPs), and evaluated quantitatively (psychometric, feasibility assessment). The HFaST was administered for 7 consecutive days to 100 individuals diagnosed with HF during a multisite, non-interventional US pilot study. Health care providers then completed a survey assessing the feasibility and importance of the HFaST in clinical practice. Qualitative development included a literature review and cognitive interviews with patients, caregivers, and HCPs. The psychometric properties of the HFaST were evaluated using classical test theory methods. Descriptive statistics provided insight into HCPs' perceptions of the feasibility of using the HFaST in clinical practice.

Results: A preliminary set of 40 items was developed for the symptom tracker and iteratively reduced to 10 items based on the qualitative phase. Test-retest reliability (weighted kappa 0.71-0.97), discriminating validity, and construct validity of the HFaST were acceptable. HCPs rated the HFaST as a good (70%) or excellent (30%) means of tracking HF symptoms. Six HFaST items were ultimately retained, covering concepts of fatigue, shortness of breath (3 items), swelling, and rapid weight gain.

Conclusions: The 6-item HFaST is an easy-to-use tool designed to raise patients' awareness of HF symptoms and facilitate communication with HCPs. Future research should evaluate HFaST implementation in clinical practice and effectiveness as an intervention to potentially prevent hospitalizations and emergency room visits.
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http://dx.doi.org/10.1186/s41687-019-0113-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497706PMC
May 2019

The Use of Eye Tracking as a Biomarker of Treatment Outcome in a Pilot Randomized Clinical Trial for Young Children with Autism.

Autism Res 2019 05 20;12(5):779-793. Epub 2019 Mar 20.

Department of Counseling, Clinical, and School Psychology, University of California Santa Barbara, Santa Barbara, California.

There is a pressing need for objective, quantifiable outcome measures in intervention trials for children with autism spectrum disorder (ASD). The current study investigated the use of eye tracking as a biomarker of treatment response in the context of a pilot randomized clinical trial of treatment for young children with ASD. Participants included 28 children with ASD, aged 18-48 months, who were randomized to one of two conditions: Pivotal Response Intervention for Social Motivation (PRISM) or community treatment as usual (TAU). Eye-tracking and behavioral assessment of developmental functioning were administered at Time 1 (prior to randomization) and at Time 2 (after 6 months of intervention). Two well-established eye-tracking paradigms were used to measure social attention: social preference and face scanning. As a context for understanding relationships between social attention and developmental ability, we first examined how scanning patterns at Time 1 were associated with concurrent developmental functioning and compared to those of 23 age-matched typically developing (TD) children. Changes in scanning patterns from Time 1 to Time 2 were then compared between PRISM and TAU groups and associated with behavioral change over time. Results showed that the social preference paradigm differentiated children with ASD from TD children. In addition, attention during face scanning was associated with language and adaptive communication skills at Time 1 and change in language skills from Time 1 to Time 2. These findings highlight the importance of examining targeted biomarkers that measure unique aspects of child functioning and that are well-matched to proposed mechanisms of change. Autism Research 2019, 12: 779-793. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Biomarkers have the potential to provide important information about how and why early interventions effect positive change for young children with ASD. The current study suggests that eye-tracking measures of social attention can be used to track change in specific areas of development, such as language, and points to the need for targeted eye-tracking paradigms designed to measure specific behavioral changes. Such biomarkers could inform the development of optimal, individualized, and adaptive interventions for young children with ASD.
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http://dx.doi.org/10.1002/aur.2093DOI Listing
May 2019

A Pilot Randomized Clinical Trial of an Enhanced Pivotal Response Treatment Approach for Young Children with Autism: The PRISM Model.

J Autism Dev Disord 2019 Jun;49(6):2358-2373

University of California Santa Barbara, Santa Barbara, CA, USA.

The symptoms of autism spectrum disorder are conceptualized to alter the quality of parent-children interactions, exposure to social learning exchanges, and ultimately the course of child development. There is evidence that modifying the procedures of Pivotal Response Treatment (PRT) to explicitly target social motivation enhances child engagement and parent-child synchrony in moment-by-moment exchanges. However, it is unclear if these within session improvements ultimately yield favorable developmental outcomes over time. The current investigation presents feasibility, utility, and preliminary efficacy data of a pilot randomized clinical trial (RCT) of a Pivotal Response Intervention for Social Motivation (PRISM) model. Data on participant factors, treatment protocol acceptability, and outcome variance and effect size are highly favorable and support the pursuit of a future, large scale RCT.
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http://dx.doi.org/10.1007/s10803-019-03909-1DOI Listing
June 2019

A Review of Patient-Reported Outcomes Labeling for Oncology Drugs Approved by the FDA and the EMA (2012-2016).

Value Health 2019 02;22(2):203-209

RTI Health Solutions, Research Triangle Park, NC, USA.

Objectives: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies.

Methods: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication.

Results: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation.

Conclusions: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews.
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http://dx.doi.org/10.1016/j.jval.2018.09.2842DOI Listing
February 2019

Inhibition of Ephrin-B2 in brain pericytes decreases cerebral pathological neovascularization in diabetic rats.

PLoS One 2019 8;14(1):e0210523. Epub 2019 Jan 8.

Biomedical Sciences Department, School of Medicine, Mercer University, Savannah, Georgia, United States of America.

We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascularization in diabetes is unclear. In the present study, we tested the hypothesis that the increased proangiogenic Ephrin-B2 signaling in PCs contributes to the dysfunctional cerebral neovascularization in diabetes. Type-II diabetes was induced by a combination of high fat diet and low dose streptozotocin injection in male Wistar rats. Selective in vivo Ephrin-B2 silencing in brain PCs was achieved using the stereotactic injection of adeno-associated virus (AAV) with NG2-promoter that expresses Ephrin-B2 shRNA. Neovascularization was assessed using vascular fluorescent dye stain. Novel object recognition (NOR) test was used to determine cognitive functions. Human brain microvascular pericytes HBMVPCs were grown in high glucose 25 mM and palmitate 200 uM (HG/Pal) to mimic diabetic conditions. Scratch migration and tube formation assays were conducted to evaluate PC/EC interaction and angiogenic functions in PC/EC co-culture. Diabetes increased the expression of Ephrin-B2 in the cerebrovasculature and pericytes. Concomitant increases in cerebral neovascularization parameters including vascular density, tortuosity and branching density in diabetic rats were accompanied by deterioration of cognitive function. Inhibition of Ephrin-B2 expression in PCs significantly restored cerebral vascularization and improved cognitive functions. HG/Pal increased PC/EC angiogenic properties in co-culture. Silencing Ephrin-B2 in PCs significantly reduced PC migration and PC/EC co-culture angiogenic properties. This study emphasizes the significant contribution of PCs to the pathological neovascularization in diabetes. Our findings introduce Ephrin-B2 signaling as a promising therapeutic target to improve cerebrovascular integrity in diabetes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0210523PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324788PMC
November 2019

Electrophysiological properties of human beta-cell lines EndoC-βH1 and -βH2 conform with human beta-cells.

Sci Rep 2018 11 19;8(1):16994. Epub 2018 Nov 19.

Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-βH1 and EndoC-βH2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca], membrane depolarisation and increased action potential firing. Similar to human primary beta cells, K channel activity is low at 1 mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the K channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca channels with some small contribution of TTX-sensitive Na channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large-conductance Ca-activated K channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electron-dense core surrounded by a thin clear halo. We conclude that the EndoC-βH1 and -βH2 cells share many features of primary human β-cells and thus represent a useful experimental model.
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http://dx.doi.org/10.1038/s41598-018-34743-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242937PMC
November 2018

Isolation, identification, and time course of human DNA typing from bed bugs, Cimex lectularius.

Forensic Sci Int 2018 Dec 18;293:1-6. Epub 2018 Oct 18.

Department of Biological Sciences, Fayetteville State University, 1200 Murchison Rd., Fayetteville, NC 28301, United States. Electronic address:

Bed bugs (Cimex lectularius L.) are ectoparasitic wingless insects that feed on the blood of mammals, typically in residential settings. The objectives of this study were to establish a time-course of human DNA quantitation from bed bugs and to generate human DNA profile(s) of a host and/or multiple hosts from a bed bug that fed on human blood. Female human genomic DNA concentrations ranged from 18.370 to 0.195ng/bed bug at 0-108h post blood meal (PBM), male human genomic DNA concentrations ranged from 5.4 to 0.105ng/bed bug at 0-108h PBM, and pooled human female and male blood ranged from 5.49 to 0.135ng/bed bug at 0-96h PBM. Human autosomal STR complete profiles were obtained until 72h PBM for female, male, and pooled human blood. These results reveal that identification of multiple human hosts is possible from a single bed bug. However, the ratio of each contributor may be variable depending on the amount of blood ingested from each individual and the time difference of blood consumed from each subject. Average peak heights for three STR markers of low (D3S1358), medium (D13S317), and high molecular weight (D2S1338), were also compared over time. Peak heights were consistently higher for the low molecular weight marker over all time intervals. These data suggest that some markers can be successfully recovered more than three days PBM. Hence, bed bugs can serve as physical evidence in temporal and spatial predictions to match suspects and/or victims to specific locations in criminal investigations.
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http://dx.doi.org/10.1016/j.forsciint.2018.10.008DOI Listing
December 2018

Type 2 diabetes risk alleles in PAM impact insulin release from human pancreatic β-cells.

Nat Genet 2018 08 27;50(8):1122-1131. Epub 2018 Jul 27.

Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.

The molecular mechanisms underpinning susceptibility loci for type 2 diabetes (T2D) remain poorly understood. Coding variants in peptidylglycine α-amidating monooxygenase (PAM) are associated with both T2D risk and insulinogenic index. Here, we demonstrate that the T2D risk alleles impact negatively on overall PAM activity via defects in expression and catalytic function. PAM deficiency results in reduced insulin content and altered dynamics of insulin secretion in a human β-cell model and primary islets from cadaveric donors. Thus, our results demonstrate a role for PAM in β-cell function, and establish molecular mechanisms for T2D risk alleles at this locus.
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http://dx.doi.org/10.1038/s41588-018-0173-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237273PMC
August 2018

Review and evaluation of patient-centered psychosocial assessments for children with central precocious puberty or early puberty.

J Pediatr Endocrinol Metab 2018 Apr;31(5):485-495

Rady Children's Hospital and University of California, San Diego, CA, USA.

The objective of this study was to assess the current use of patient-centered psychosocial assessments for the evaluation of children with central precocious puberty (CPP). Studies evaluating the psychosocial impact of CPP were identified through searches of the PubMed and Cochrane Library databases, ClinicalTrials.gov, a drug prescribing information database, and regulatory websites. Studies were screened using prespecified inclusion and exclusion criteria. Potentially relevant patient-centered outcome assessments (including patient-, parent- or observer-reported measures) used in the identified studies were evaluated in detail for their relevance in CPP. Of the 467 studies identified, 15 met the inclusion criteria. Frequently assessed concepts included depression and anxiety, behavior and behavioral problems, body image and self-esteem and personality type/characteristics. Among the assessments used in the identified studies, the Child Behavior Checklist, Pediatric Quality of Life Inventory (PedsQL), SF-10 for Children and Child Health Questionnaire were comprehensively evaluated. The PedsQL showed promise as a patient-centered outcome measure in CPP. Although there is a lack of validated tools measuring psychosocial health and health-related quality of life in patients with CPP, the PedsQL captures issues seen in this patient population and is relatively easy to administer. Further studies using this and other tools in children with CPP are needed.
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http://dx.doi.org/10.1515/jpem-2017-0465DOI Listing
April 2018

Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci.

Elife 2018 02 7;7. Epub 2018 Feb 7.

The Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including ) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.
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http://dx.doi.org/10.7554/eLife.31977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828664PMC
February 2018

Genes Associated with Pancreas Development and Function Maintain Open Chromatin in iPSCs Generated from Human Pancreatic Beta Cells.

Stem Cell Reports 2017 11 1;9(5):1395-1405. Epub 2017 Nov 1.

Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Current in vitro islet differentiation protocols suffer from heterogeneity and low efficiency. Induced pluripotent stem cells (iPSCs) derived from pancreatic beta cells (BiPSCs) preferentially differentiate toward endocrine pancreas-like cells versus those from fibroblasts (FiPSCs). We interrogated genome-wide open chromatin in BiPSCs and FiPSCs via ATAC-seq and identified ∼8.3k significant, differential open chromatin sites (DOCS) between the two iPSC subtypes (false discovery rate [FDR] < 0.05). DOCS where chromatin was more accessible in BiPSCs (Bi-DOCS) were significantly enriched for known regulators of endodermal development, including bivalent and weak enhancers, and FOXA2 binding sites (FDR < 0.05). Bi-DOCS were associated with genes related to pancreas development and beta-cell function, including transcription factors mutated in monogenic diabetes (PDX1, NKX2-2, HNF1A; FDR < 0.05). Moreover, Bi-DOCS correlated with enhanced gene expression in BiPSC-derived definitive endoderm and pancreatic progenitor cells. Bi-DOCS therefore highlight genes and pathways governing islet-lineage commitment, which can be exploited for differentiation protocol optimization, diabetes disease modeling, and therapeutic purposes.
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http://dx.doi.org/10.1016/j.stemcr.2017.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831005PMC
November 2017

Payer Perspectives on Patient-Reported Outcomes in Health Care Decision Making: Oncology Examples.

J Manag Care Spec Pharm 2017 Feb;23(2):125-134

1 RTI Health Solutions, Research Triangle Park, North Carolina.

Background: Health authorities and payers increasingly recognize the importance of patient perspectives and patient-reported outcomes (PROs) in health care decision making. However, given the broad variety of PRO endpoints included in clinical programs and variations in the timing of PRO data collection and country-specific needs, the role of PRO data in reimbursement decisions requires characterization.

Objectives: To (a) determine the effect of PRO data on market access and reimbursement decisions for oncology products in multiple markets and (b) assess the effect of PRO data collected after clinical progression on payer decision making.

Methods: A 3-part assessment (targeted literature review, qualitative one-on-one interviews, and online survey) was undertaken. Published literature was identified through searches in PubMed/MEDLINE and Embase. In addition, a targeted search was conducted of health technology assessment (HTA) agency websites in the United States, the United Kingdom, France, and Germany. Qualitative one-on-one interviews were conducted with 16 payers from the RTI Health Solutions global advisory panel in 14 markets (Australia, Brazil, France, Germany, Italy, South Korea, Netherlands, Poland, Spain, Sweden, Taiwan, Turkey, the United Kingdom, and the United States [n = 3]). Of the 200 payers and payer advisors from the global advisory panel invited to participate in the online survey, 20 respondents (China, France, Germany, Spain [n = 2], Taiwan, the United Kingdom, and the United States [n = 13]) completed the survey, and 6 respondents (Australia, South Korea, and the United States [n = 4]) partially completed the survey.

Results: Reviews of the literature and publicly available HTAs and reimbursement decisions suggested that HTA bodies and payers have varying experience with and confidence in PRO data. Payers participating in the survey indicated that PRO data may be especially influential in oncology compared with other therapeutic areas. Payers surveyed offered little differentiation by cancer type in the importance of PRO data but felt that it was most important to collect PRO data in phase 3 and postmarketing studies. Payers surveyed also anticipated an increasing significance for PRO data over the next 5-10 years. Characteristics of PRO data that maximize influence on payer decision making were reported to be (a) quality, well-controlled, and transparent PRO evidence; (b) psychometric validation of the PRO measure in targeted populations; and (c) publication in peer-reviewed journals. In markets with decentralized health care decision making, PRO data currently have more influence at the local level. Inclusion of PRO data in cancer treatment guidelines is key for centralized markets. Payers surveyed generally considered collecting PRO data postprogression to be useful. Of the 16 interviewees, 11 indicated that it is worthwhile to collect PRO data postprogression and that positive PRO data may support continued therapy at the physician's discretion upon regulatory approval, even in progressive disease.

Conclusions: PRO data may help to differentiate treatments, particularly after clinical progression in oncology. Payers worldwide recognize high-quality PRO data as a key component of their decision-making process and anticipate the growing importance of PRO data in the future.

Disclosures: This study and preparation of this article were funded by Novartis Pharmaceuticals. This research was performed under a research contract between RTI Health Solutions and Novartis Pharmaceuticals. Brogan, Hogue, Demuro, and Barrett are employees of RTI Health Solutions. D'Alessio and Bal are employees of Novartis Pharmaceuticals. Study concept and design were contributed by DeMuro, Barrett, Bal, and Hogue. Brogan and Hogue took the lead in data collection, assisted by DeMuro and Bal. Data interpretation was performed by Brogan and Hogue, assisted by the other authors. The manuscript was written by D'Alessio and Brogan, along with the other authors, and revised primarily by Brogan, along with Hogue and assisted by the other authors. The abstract for this article was presented as a research poster at the following meetings: Hogue SL, Brogan A P, De Muro C, D'Alessio D, Bal V. Patient-reported outcomes (PRO) in post-progression oncology: implications in health technology assessments and payer decision making. Poster presented at the ISPOR 18th Annual European Meeting; November 7-11, 2015. Milan, Italy. Hogue SL, Brogan AP, De Muro C, D'Alessio D, Bal V. Influence of patient-reported outcomes (PRO) on market access decisions in markets with centralized healthcare systems. Poster presented at the ISPOR 18th Annual European Meeting; November 7-11, 2015. Milan, Italy. Hogue SL, Brogan AP, De Muro C, Barrett A, D'Alessio D, Bal V. Influence of patient-reported outcomes on market access decisions in decentralized markets (Brazil, Italy, Spain and the United States). Poster presented at the ISPOR 20th Annual Meeting; May 16-20, 2015. Philadelphia PA. Hogue SL, Brogan A P, De Muro C, Barrett A, McLeod L, D'Alessio D, et al. Payer Perspectives of Patient-Reported Outcomes Data: An Online Assessment. Poster presented at the ISOQOL 22nd Annual Meeting; October 21-24, 2015. Vancouver, British Columbia, Canada.
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http://dx.doi.org/10.18553/jmcp.2017.23.2.125DOI Listing
February 2017

Systematic Functional Characterization of Candidate Causal Genes for Type 2 Diabetes Risk Variants.

Diabetes 2016 Dec 23;65(12):3805-3811. Epub 2016 Aug 23.

Oxford Centre for Diabetes, Endocrinology & Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, U.K.

Most genetic association signals for type 2 diabetes risk are located in noncoding regions of the genome, hindering translation into molecular mechanisms. Physiological studies have shown a majority of disease-associated variants to exert their effects through pancreatic islet dysfunction. Systematically characterizing the role of regional transcripts in β-cell function could identify the underlying disease-causing genes, but large-scale studies in human cellular models have previously been impractical. We developed a robust and scalable strategy based on arrayed gene silencing in the human β-cell line EndoC-βH1. In a screen of 300 positional candidates selected from 75 type 2 diabetes regions, each gene was assayed for effects on multiple disease-relevant phenotypes, including insulin secretion and cellular proliferation. We identified a total of 45 genes involved in β-cell function, pointing to possible causal mechanisms at 37 disease-associated loci. The results showed a strong enrichment for genes implicated in monogenic diabetes. Selected effects were validated in a follow-up study, including several genes (ARL15, ZMIZ1, and THADA) with previously unknown or poorly described roles in β-cell biology. We have demonstrated the feasibility of systematic functional screening in a human β-cell model and successfully prioritized plausible disease-causing genes at more than half of the regions investigated.
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http://dx.doi.org/10.2337/db16-0361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402869PMC
December 2016

Insights into islet development and biology through characterization of a human iPSC-derived endocrine pancreas model.

Islets 2016 04;8(3):83-95

f Department of Islet and Stem Cell Biology , Novo Nordisk A/S , Maaloev , Denmark.

Directed differentiation of stem cells offers a scalable solution to the need for human cell models recapitulating islet biology and T2D pathogenesis. We profiled mRNA expression at 6 stages of an induced pluripotent stem cell (iPSC) model of endocrine pancreas development from 2 donors, and characterized the distinct transcriptomic profiles associated with each stage. Established regulators of endodermal lineage commitment, such as SOX17 (log2 fold change [FC] compared to iPSCs = 14.2, p-value = 4.9 × 10(-5)) and the pancreatic agenesis gene GATA6 (log2 FC = 12.1, p-value = 8.6 × 10(-5)), showed transcriptional variation consistent with their known developmental roles. However, these analyses highlighted many other genes with stage-specific expression patterns, some of which may be novel drivers or markers of islet development. For example, the leptin receptor gene, LEPR, was most highly expressed in published data from in vivo-matured cells compared to our endocrine pancreas-like cells (log2 FC = 5.5, p-value = 2.0 × 10(-12)), suggesting a role for the leptin pathway in the maturation process. Endocrine pancreas-like cells showed significant stage-selective expression of adult islet genes, including INS, ABCC8, and GLP1R, and enrichment of relevant GO-terms (e.g. "insulin secretion"; odds ratio = 4.2, p-value = 1.9 × 10(-3)): however, principal component analysis indicated that in vitro-differentiated cells were more immature than adult islets. Integration of the stage-specific expression information with genetic data from T2D genome-wide association studies revealed that 46 of 82 T2D-associated loci harbor genes present in at least one developmental stage, facilitating refinement of potential effector transcripts. Together, these data show that expression profiling in an iPSC islet development model can further understanding of islet biology and T2D pathogenesis.
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http://dx.doi.org/10.1080/19382014.2016.1182276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987020PMC
April 2016

Population whole-genome bisulfite sequencing across two tissues highlights the environment as the principal source of human methylome variation.

Genome Biol 2015 Dec 23;16:290. Epub 2015 Dec 23.

Department of Human Genetics, McGill University, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, Quebec, Canada.

Background: CpG methylation variation is involved in human trait formation and disease susceptibility. Analyses within populations have been biased towards CpG-dense regions through the application of targeted arrays. We generate whole-genome bisulfite sequencing data for approximately 30 adipose and blood samples from monozygotic and dizygotic twins for the characterization of non-genetic and genetic effects at single-site resolution.

Results: Purely invariable CpGs display a bimodal distribution with enrichment of unmethylated CpGs and depletion of fully methylated CpGs in promoter and enhancer regions. Population-variable CpGs account for approximately 15-20 % of total CpGs per tissue, are enriched in enhancer-associated regions and depleted in promoters, and single nucleotide polymorphisms at CpGs are a frequent confounder of extreme methylation variation. Differential methylation is primarily non-genetic in origin, with non-shared environment accounting for most of the variance. These non-genetic effects are mainly tissue-specific. Tobacco smoking is associated with differential methylation in blood with no evidence of this exposure impacting cell counts. Opposite to non-genetic effects, genetic effects of CpG methylation are shared across tissues and thus limit inter-tissue epigenetic drift. CpH methylation is rare, and shows similar characteristics of variation patterns as CpGs.

Conclusions: Our study highlights the utility of low pass whole-genome bisulfite sequencing in identifying methylome variation beyond promoter regions, and suggests that targeting the population dynamic methylome of tissues requires assessment of understudied intergenic CpGs distal to gene promoters to reveal the full extent of inter-individual variation.
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http://dx.doi.org/10.1186/s13059-015-0856-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699357PMC
December 2015

Transcript Expression Data from Human Islets Links Regulatory Signals from Genome-Wide Association Studies for Type 2 Diabetes and Glycemic Traits to Their Downstream Effectors.

PLoS Genet 2015 Dec 1;11(12):e1005694. Epub 2015 Dec 1.

Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, United Kingdom.

The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. ‎At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci.
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http://dx.doi.org/10.1371/journal.pgen.1005694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666611PMC
December 2015

Loss-of-Function Mutations in the Cell-Cycle Control Gene CDKN2A Impact on Glucose Homeostasis in Humans.

Diabetes 2016 Feb 5;65(2):527-33. Epub 2015 Nov 5.

Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, U.K. Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, U.K.

At the CDKN2A/B locus, three independent signals for type 2 diabetes risk are located in a noncoding region near CDKN2A. The disease-associated alleles have been implicated in reduced β-cell function, but the underlying mechanism remains elusive. In mice, β-cell-specific loss of Cdkn2a causes hyperplasia, while overexpression leads to diabetes, highlighting CDKN2A as a candidate effector transcript. Rare CDKN2A loss-of-function mutations are a cause of familial melanoma and offer the opportunity to determine the impact of CDKN2A haploinsufficiency on glucose homeostasis in humans. To test the hypothesis that such individuals have improved β-cell function, we performed oral and intravenous glucose tolerance tests on mutation carriers and matched control subjects. Compared with control subjects, carriers displayed increased insulin secretion, impaired insulin sensitivity, and reduced hepatic insulin clearance. These results are consistent with a model whereby CDKN2A loss affects a range of different tissues, including pancreatic β-cells and liver. To test for direct effects of CDKN2A-loss on β-cell function, we performed knockdown in a human β-cell line, EndoC-bH1. This revealed increased insulin secretion independent of proliferation. Overall, we demonstrated that CDKN2A is an important regulator of glucose homeostasis in humans, thus supporting its candidacy as an effector transcript for type 2 diabetes-associated alleles in the region.
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http://dx.doi.org/10.2337/db15-0602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724950PMC
February 2016

Genetic studies of body mass index yield new insights for obesity biology.

Nature 2015 Feb;518(7538):197-206

Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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http://dx.doi.org/10.1038/nature14177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382211PMC
February 2015

New genetic loci link adipose and insulin biology to body fat distribution.

Nature 2015 Feb;518(7538):187-196

Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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http://dx.doi.org/10.1038/nature14132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338562PMC
February 2015

A comprehensive review of nongenetic prognostic and predictive factors influencing the heterogeneity of outcomes in advanced non-small-cell lung cancer.

Cancer Manag Res 2014 23;6:437-49. Epub 2014 Oct 23.

Eli Lilly and Company, Indianapolis, IN, USA.

While there have been advances in treatment options for those with advanced non-small-cell lung cancer, unmet medical needs remain, partly due to the heterogeneity of treatment effect observed among patients. The goals of this literature review were to provide updated information to complement past reviews and to identify a comprehensive set of nongenetic prognostic and predictive baseline factors that may account for heterogeneity of outcomes in advanced non-small-cell lung cancer. A review of the literature between 2000 and 2010 was performed using PubMed, Embase, and Cochrane Library. All relevant studies that met the inclusion criteria were selected and data elements were abstracted. A classification system was developed to evaluate the level of evidence for each study. A total of 54 studies were selected for inclusion. Patient-related factors (eg, performance status, sex, and age) were the most extensively researched nongenetic prognostic factors, followed by disease stage and histology. Moderately researched prognostic factors were weight-related variables and number or site of metastases, and the least studied were comorbidities, previous therapy, smoking status, hemoglobin level, and health-related quality of life/symptom severity. The prognostic factors with the most consistently demonstrated associations with outcomes were performance status, number or site of metastases, previous therapy, smoking status, and health-related quality of life. Of the small number of studies that assessed predictive factors, those that were found to be significantly predictive of outcomes were performance status, age, disease stage, previous therapy, race, smoking status, sex, and histology. These results provide a comprehensive overview of nongenetic prognostic and predictive factors assessed in advanced non-small-cell lung cancer over the last decade. This information can be used to inform the design of future clinical trials by suggesting additional subgroups based on nongenetic factors that may be analyzed to further investigate potential prognostic and predictive factors.
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http://dx.doi.org/10.2147/CMAR.S63603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211870PMC
November 2014

Defining the role of common variation in the genomic and biological architecture of adult human height.

Nat Genet 2014 Nov 5;46(11):1173-86. Epub 2014 Oct 5.

Department of Genetic Epidemiology, Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the 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 60% of heritability. The 697 variants clustered in 423 loci were 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/β-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.
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http://dx.doi.org/10.1038/ng.3097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250049PMC
November 2014

Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.

Hum Mol Genet 2014 Dec 11;23(24):6432-40. Epub 2014 Jul 11.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK, Molecular Genetics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.

Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.
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http://dx.doi.org/10.1093/hmg/ddu360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240195PMC
December 2014

Evaluation of common type 2 diabetes risk variants in a South Asian population of Sri Lankan descent.

PLoS One 2014 13;9(6):e98608. Epub 2014 Jun 13.

Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; Oxford National Institute for Health Research Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.

Introduction: Most studies seeking common variant associations with type 2 diabetes (T2D) have focused on individuals of European ancestry. These discoveries need to be evaluated in other major ancestral groups, to understand ethnic differences in predisposition, and establish whether these contribute to variation in T2D prevalence and presentation. This study aims to establish whether common variants conferring T2D-risk in Europeans contribute to T2D-susceptibility in the South Asian population of Sri Lanka.

Methodology: Lead single nucleotide polymorphism (SNPs) at 37 T2D-risk loci attaining genome-wide significance in Europeans were genotyped in 878 T2D cases and 1523 normoglycaemic controls from Sri Lanka. Association testing was performed by logistic regression adjusting for age and sex and by the Cochran-Mantel-Haenszel test after stratifying according to self-identified ethnolinguistic subgroup. A weighted genetic risk score was generated to examine the combined effect of these SNPs on T2D-risk in the Sri Lankan population.

Results: Of the 36 SNPs passing quality control, sixteen showed nominal (p<0.05) association in Sri Lankan samples, fifteen of those directionally-consistent with the original signal. Overall, these association findings were robust to analyses that accounted for membership of ethnolinguistic subgroups. Overall, the odds ratios for 31 of the 36 SNPs were directionally-consistent with those observed in Europeans (p = 3.2×10(-6)). Allelic odds ratios and risk allele frequencies in Sri Lankan subjects were not systematically different to those reported in Europeans. Genetic risk score and risk of T2D were strongly related in Sri Lankans (per allele OR 1.10 [95%CI 1.08-1.13], p = 1.2×10(-17)).

Conclusion: Our data indicate that most T2D-risk variants identified in Europeans have similar effects in South Asians from Sri Lanka, and that systematic difference in common variant associations are unlikely to explain inter-ethnic differences in prevalence or presentation of T2D.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098608PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057178PMC
October 2015
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