G I Bell

University of Chicago, Chicago, Illinois, United States

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Publications (506)4450.9 Total impact

  • Endocrinology: Adult and Pediatric, 01/2016: pages 527-545.e6; , ISBN: 9780323189071
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    ABSTRACT: Staphylococcus aureus is the number one cause of hospital-acquired infections. Understanding host pathogen interactions is paramount to the development of more effective treatment and prevention strategies. Therefore, whole exome sequence and chip-based genotype data were used to conduct rare variant and genome-wide association analyses in a Mexican-American cohort from Starr County, Texas to identify genes and variants associated with S. aureus nasal carriage. Unlike most studies of S. aureus that are based on hospitalized populations, this study used a representative community sample. Two nasal swabs were collected from participants (n = 858) 11-17 days apart between October 2009 and December 2013, screened for the presence of S. aureus, and then classified as either persistent, intermittent, or non-carriers. The chip-based and exome sequence-based single variant association analyses identified 1 genome-wide significant region (KAT2B) for intermittent and 11 regions suggestively associated with persistent or intermittent S. aureus carriage. We also report top findings from gene-based burden analyses of rare functional variation. Notably, we observed marked differences between signals associated with persistent and intermittent carriage. In single variant analyses of persistent carriage, 7 of 9 genes in suggestively associated regions and all 5 top gene-based findings are associated with cell growth or tight junction integrity or are structural constituents of the cytoskeleton, suggesting that variation in genes associated with persistent carriage impact cellular integrity and morphology.
    PLoS ONE 11/2015; 10(11):e0142130. DOI:10.1371/journal.pone.0142130 · 3.23 Impact Factor
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    ABSTRACT: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry (http://monogenicdiabetes.uchicago.edu). The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of Medical Genetics 06/2015; 52(9). DOI:10.1136/jmedgenet-2015-103220 · 6.34 Impact Factor
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    ABSTRACT: Non-obese diabetic (NOD) mice are a commonly-used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra high performance liquid chromatography accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry -based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1000 circulating lipids and metabolites in male and female progressor and non-progressor animals (n=71). Statistical and multivariate analyses were used to identify age- and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and non-progressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono delta lactone and galactonic acid, and reductions in cysteine methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceremia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D. Copyright © 2015, American Journal of Physiology - Endocrinology and Metabolism.
    AJP Endocrinology and Metabolism 04/2015; 308(11):ajpendo.00019.2015. DOI:10.1152/ajpendo.00019.2015 · 3.79 Impact Factor
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    ABSTRACT: Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5x10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
    PLoS Genetics 01/2015; 11(1). DOI:10.1371/journal.pgen.1004876 · 7.53 Impact Factor
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    Louis H Philipson · Graeme Bell · Kenneth S Polonsky ·

    Proceedings of the National Academy of Sciences 01/2015; 112(4). DOI:10.1073/pnas.1423774112 · 9.67 Impact Factor
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    ABSTRACT: Non-coding variation within TCF7L2 remains the strongest genetic determinant of type 2 diabetes risk in humans. A considerable effort has been placed in understanding the functional roles of TCF7L2 in pancreatic beta cells, despite evidence of TCF7L2 expression in various peripheral tissues important in glucose homeostasis. Here, we use a humanized mouse model overexpressing Tcf7l2, resulting in glucose intolerance, to infer the contribution of Tcf7l2 overexpression in beta cells and in other tissues to the metabolic phenotypes displayed by these mice. Restoring Tcf7l2 expression specifically in beta cells to endogenous levels, in face of its overexpression elsewhere, results in impaired insulin secretion, reduced beta cell number and islet area, corroborating data obtained in humans showing similar phenotypes as a result of manipulations leading to Tcf7l2 loss of function. Interestingly, the persistent overexpression of Tcf7l2 in non-pancreatic tissues results in a significant worsening in glucose tolerance in vivo, indicating that Tcf7l2 overexpression in beta cells does not account for the glucose intolerance in the Tcf7l2 overexpression mouse model. Collectively, these data posit that Tcf7l2 plays key roles in glucose metabolism through actions beyond pancreatic beta cells, and further points to functionally opposing cell-type specific effects for Tcf7l2 on the maintenance of balanced glucose metabolism, thereby urging a careful examination of its role in non-pancreatic tissues as well as its composite metabolic effects across distinct tissues. Uncovering these roles may lead to new therapeutic targets for type 2 diabetes.
    Human Molecular Genetics 11/2014; 24(6). DOI:10.1093/hmg/ddu577 · 6.39 Impact Factor
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    ABSTRACT: Advances of modern sensing and sequencing technologies generate a deluge of high dimensional space-temporal physiological and next-generation sequencing (NGS) data. Physiological traits are observed either as continuous random functions, or on a dense grid and referred to as function-valued traits. Both physiological and NGS data are highly correlated data with their inherent order, spacing, and functional nature which are ignored by traditional summary-based univariate and multivariate regression methods designed for quantitative genetic analysis of scalar trait and common variants. To capture morphological and dynamic features of the data and utilize their dependent structure, we propose a functional linear model (FLM) in which a trait curve is modeled as a response function, the genetic variation in a genomic region or gene is modeled as a functional predictor, and the genetic effects are modeled as a function of both time and genomic position (FLMF) for genetic analysis of function-valued trait with both GWAS and NGS data. By extensive simulations, we demonstrate that the FLMF has the correct type 1 error rates and much higher power to detect association than the existing methods. The FLMF is applied to sleep data from Starr County health studies where oxygen saturation were measured in 22,670 seconds on average for 833 individuals. We found 65 genes that were significantly associated with oxygen saturation functional trait with P-values ranging from 2.40E-06 to 2.53E-21. The results clearly demonstrate that the FLMF substantially outperforms the traditional genetic models with scalar trait.
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    ABSTRACT: IMPORTANCE Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14 276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10-7) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.
    Journal of the American Medical Association 06/2014; 22(22):2305-2314. DOI:10.1001/jama.2014.6511
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    ABSTRACT: Mutations in pancreatic duodenal homeobox (PDX1) are associated with diabetes in humans. Pdx1-haploinsufficient mice develop diabetes due to an increase in β-cell death leading to reduced β-cell mass. In order to define the molecular link between Pdx1 deficiency and β-cell death, Pdx1 haploinsufficient mice in which the genes for the BH3-only molecules Bim and Puma had been ablated were studied on a high fat diet. Compared to Pdx1(+/-) mice, animals haploinsufficient for both Pdx1 and Bim or Puma genes showed improved glucose tolerance, enhanced β-cell mass and reduction in the number of TUNEL positive cells in islets. These results suggest that Bim and Puma ablation improves β-cell survival in Pdx1(+/-) mice. To explore the mechanisms responsible for these findings Pdx1 gene expression was knocked down in mouse MIN6 insulinoma cells resulting in apoptotic cell death that was found to be associated with increased expression of BH3-only molecules Bim and Puma. If the upregulation of Bim and Puma that occurs during Pdx1 suppression was prevented, apoptotic β-cell death was reduced in vitro. These results suggest that Bim and Puma play important role in β-cell apoptosis in Pdx1-deficient diabetes.
    Diabetes 03/2014; 63(8). DOI:10.2337/db13-1513 · 8.10 Impact Factor
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    ABSTRACT: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
    Nature Genetics 03/2014; · 29.35 Impact Factor
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    ABSTRACT: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
    Nature Genetics 03/2014; 46(3):234-244. DOI:10.1038/ng.2897 · 29.35 Impact Factor

  • Diabetes Technology &amp Therapeutics 02/2014; 16:A23-A23. · 2.11 Impact Factor
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    ABSTRACT: The identification and validation of gene-gene interactions is a major challenge in human studies. Here, we explore an approach for studying epistasis in humans using a Drosophila melanogaster model of neonatal diabetes mellitus. Expression of the mutant preproinsulin (hINS(C96Y)) in the eye imaginal disc mimics the human disease: it activates conserved stress response pathways and leads to cell death (reduction in eye area). Dominant-acting variants in wild-derived inbred lines from the Drosophila Genetics Reference Panel produce a continuous, highly heritable distribution of eye degeneration phenotypes in a hINS(C96Y) background. A genome-wide association study (GWAS) in 154 sequenced lines identified a sharp peak on chromosome 3L, which mapped to a 400bp linkage block within an intron of the gene sulfateless (sfl). RNAi knock-down of sfl enhanced the eye degeneration phenotype in a mutant-hINS-dependent manner. RNAi against two additional genes in the heparan sulfate (HS) biosynthetic pathway (ttv and botv), in which sfl acts, also modified the eye phenotype in a hINS(C96Y)-dependent manner, strongly suggesting a novel link between HS-modified proteins and cellular responses to misfolded proteins. Finally, we evaluated allele-specific expression difference between the two major sfl-intronic haplotypes in heterozygtes. The results showed significant heterogeneity in marker-associated gene expression, thereby leaving the causal mutation(s) and its mechanism unidentified. In conclusion, the ability to create a model of human genetic disease, map a QTL by GWAS to a specific gene, validate its contribution to disease with available genetic resources, and the potential to experimentally link the variant to a molecular mechanism, demonstrate the many advantages Drosophila holds in determining the genetic underpinnings of human disease.
    Genetics 02/2014; 196(2):557-567. DOI:10.1534/genetics.113.157800 · 5.96 Impact Factor
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    ABSTRACT: Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
    Nature 12/2013; 506(7486). DOI:10.1038/nature12828 · 41.46 Impact Factor
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    ABSTRACT: Drosophila melanogaster has been widely used as models of human Mendelian disease, but its value in modeling complex disease has received little attention. Fly models of complex disease would enable high-resolution mapping of disease-modifying loci and the identification of novel targets for therapeutic intervention. Here, we describe a fly model of permanent neonatal diabetes mellitus and explore the complexity of this model. The approach involves the transgenic expression of a misfolded mutant of human preproinsulin, hINS(C96Y), which is a cause of permanent neonatal diabetes. When expressed in fly imaginal discs, hINS(C96Y) causes a reduction of adult structures, including the eye, wing and notum. Eye imaginal discs exhibit defects in both the structure and arrangement of ommatidia. In the wing, expression of hINS(C96Y) leads to ectopic expression of veins and mechano-sensory organs, indicating disruption of wild type signaling processes regulating cell fates. These readily measurable "disease" phenotypes are sensitive to temperature, gene dose and sex. Mutant (but not wild type) proinsulin expression in the eye imaginal disc induces IRE1-mediated XBP1 alternative splicing, a signal for endoplasmic reticulum (ER) stress response activation, and produces global change in gene expression. Mutant hINS transgene tester strains, when crossed to stocks from the Drosophila Genetic Reference Panel (DGRP) produce F1 adults with a continuous range of disease phenotypes and large broad-sense heritability. Surprisingly, the severity of mutant hINS-induced disease in the eye is not correlated with that in the notum in these crosses, nor with eye reduction phenotypes caused by the expression of two dominant eye mutants acting in two different eye development pathways, Drop (Dr) or Lobe (L) when crossed into the same genetic backgrounds. The tissue specificity of genetic variability for mutant hINS-induced disease has, therefore, its own distinct signature. The genetic dominance of disease-specific phenotypic variability in our model of misfolded human proinsulin makes this approach amenable to genome-wide association study (GWAS) in a simple F1 screen of natural variation.
    Genetics 11/2013; 196(2). DOI:10.1534/genetics.113.157602 · 5.96 Impact Factor
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    ABSTRACT: Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.
    Pediatric Diabetes 10/2013; 15(3). DOI:10.1111/pedi.12086 · 2.57 Impact Factor
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    ABSTRACT: Objective To evaluate the cost-effectiveness of a genetic testing policy for HNF1A, HNF4A and GCK-MODY in a hypothetical cohort of type 2 diabetes patients 25-40 years old with a MODY prevalence of 2%.Research Design and Methods We used a simulation model of type 2 diabetes complications based on UKPDS data, modified to account for the natural history of disease by genetic subtype, to compare a policy of genetic testing at diabetes diagnosis versus a policy of no testing. Under the screening policy, successful sulfonylurea treatment of HNF1A-MODY and HNF4A-MODY was modeled to produce a glycosylated hemoglobin reduction of -1.5%, compared to usual care. GCK-MODY received no therapy. Main outcome measures were costs and quality-adjusted life years (QALYs), based on lifetime risk of complications and treatments, expressed as the incremental cost-effectiveness ratio (ICER, $/QALY).ResultsThe testing policy yielded an average gain of 0.012 QALYs and resulted in an ICER of $205,000. Sensitivity analysis showed that if the MODY prevalence was 6%, the ICER would be ∼$50,000. If MODY prevalence was >30%, the testing policy was cost-saving. Reducing genetic testing costs to $700 also resulted in an ICER of ∼$50,000.Conclusions Our simulated model suggests a policy of testing for MODY in selected populations is cost-effective for the United States based on contemporary ICER thresholds. Higher prevalence of MODY in the tested population or decreased testing costs would enhance cost-effectiveness. Our results make a compelling argument for routine coverage of genetic testing in patients with high clinical suspicion of MODY.
    Diabetes care 09/2013; 37(1). DOI:10.2337/dc13-0410 · 8.42 Impact Factor

Publication Stats

40k Citations
4,450.90 Total Impact Points


  • 1987-2015
    • University of Chicago
      • • Department of Medicine
      • • Department of Human Genetics
      • • Department of Biochemistry & Molecular Biology
      • • Department of Obstetrics & Gynecology
      • • Department of Pharmacological and Physiological Sciences
      Chicago, Illinois, United States
  • 2011
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
  • 1997-2010
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • Steno Diabetes Center
      Gjentofte, Capital Region, Denmark
  • 2005
    • The University of the West Indies, Trinidad and Tobago
      • Department of Life Sciences
      City of Port-of-Spain, City of Port of Spain, Trinidad and Tobago
  • 1988-2005
    • Vanderbilt University
      • • Department of Molecular Physiology and Biophysics
      • • Department of Biochemistry
      Nashville, Michigan, United States
  • 1987-2005
    • Howard Hughes Medical Institute
      • Molecular Biology Facility
      Ashburn, Virginia, United States
  • 2004
    • The Chinese University of Hong Kong
      • Prince of Wales Hospital
      Hong Kong, Hong Kong
  • 2001-2004
    • University of Bergen
      • Department of Clinical Medicine
      Bergen, Hordaland Fylke, Norway
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2002
    • Tokyo Women's Medical University
      • Diabetes Center
      Edo, Tōkyō, Japan
  • 1997-2001
    • University of Exeter
      • Peninsula College of Medicine and Dentistry
      Exeter, England, United Kingdom
  • 1999
    • Institut de Biologie de Lille
      Lille, Nord-Pas-de-Calais, France
  • 1998
    • Haukeland University Hospital
      • Department of Pediatrics
      Bergen, Hordaland, Norway
  • 1996-1997
    • The Rockefeller University
      New York, New York, United States
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
  • 1995
    • Virginia Mason Medical Center
      Seattle, Washington, United States
    • Institut Louis Bachelier
      Lutetia Parisorum, Île-de-France, France
    • Tulane University
      New Orleans, Louisiana, United States
  • 1994
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
  • 1976-1994
    • University of California, San Francisco
      • Department of Biochemistry and Biophysics
      San Francisco, California, United States
    • CSU Mentor
      Long Beach, California, United States
  • 1993
    • Kyoto University
      • Graduate School of Medicine / Faculty of Medicine
      Kioto, Kyōto, Japan
    • University of Pennsylvania
      • Department of Pharmacology
      Filadelfia, Pennsylvania, United States
  • 1990-1992
    • Oxford University Hospitals NHS Trust
      • Department of Haematology
      Oxford, England, United Kingdom
  • 1991
    • University of Glasgow
      • Division of Biochemistry
      Glasgow, SCT, United Kingdom
  • 1989
    • Wayne State University
      • School of Medicine
      Detroit, Michigan, United States
    • Karolinska University Hospital
      • Department of Clinical Genetics
      Stockholm, Stockholm, Sweden
  • 1986-1988
    • University of Iowa
      • Department of Pediatrics
      Iowa City, IA, United States
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1985-1987
    • Roswell Park Cancer Institute
      • Department of Human Genetics
      Buffalo, New York, United States
    • Hokkaido University
      • Laboratory of Molecular Enzymology
      Sapporo, Hokkaidō, Japan
    • Washington University in St. Louis
      • Department of Medicine
      San Luis, Missouri, United States
  • 1983
    • Eli Lilly
      Indianapolis, Indiana, United States