Steve Lewitzky

Novartis (United States)

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Joanne M. Meyer

Mount Sinai Hospital

Alan Permutt

Washington University in St. Louis

Leif Groop

Lund University

Jeanette McCarthy

Duke University

Thomas Lehner

New York Genome Center

Cynthia Reeves

Cell Signaling Technology (United States)

Phillip Bretsky

University of Southern California

Chih‐Chieh Wu

National Cheng Kung University

David Altshuler

University of Michigan–Ann Arbor

Daniel E. Weeks

University of Pittsburgh

Cooperative Institutions

Harvard University

Novartis (Switzerland)

Universidad de Costa Rica

Massachusetts General Hospital

University of California, San Francisco

Millennium Engineering and Integration (United States)

Broad Institute

Novartis (United States)

Brigham and Women's Hospital

University of Southern California

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Polymorphisms of the HDL Receptor Gene Associated with HDL Cholesterol Levels in Diabetic Kindred from Three Populations

Human Heredity (2003)

Jeanette McCarthy Steve Lewitzky Cynthia Reeves Alan Permutt Benjamin Gläser

Objective: We examined polymorphisms in the HDL receptor, SR-BI, for association with plasma HDL cholesterol levels. Methods: Study subjects, including 847 women and 725 men, were from families originally ascertained for type 2 diabetes from Finland, Sweden and Israel. Four common polymorphisms were examined in linear regression analysis: an exon 1 missense (EX1), exon 8 silent (EX8), intron 5 (IVS5) and intron 10 (IVS10) variants. Results: Genotype combinations for the three polymorphisms in linkage disequilibrium (IVS5, EX8 and IVS10) were found to be associated with HDL-C among women from the Israeli (p = 0.01) and Swedish (p = 0.06) populations. In Finnish women, the association was only apparent after taking into account effect modification by triglyceride levels (p = 0.04). One specific pattern of genotypes, denoted by presence of the IVS5_T and EX8_C alleles, and absence of the IVS10_G allele, was consistently associated with the lowest mean levels of HDL-C in women from all three populations. These same associations were not found in men. Conclusions: Polymorphic variation of the SR-BI gene may influence HDL-C levels and act in a sex-dependent manner.

Linkage Disequilibrium

10.1159/000073986

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Citations (32)

Assessment of Weighting Methodology for the National Comorbidity Survey

American Journal of Epidemiology (1997)

R. J. A. Little Steve Lewitzky Steven G. Heeringa James M. Lepkowski Ronald C. Kessler

The authors studied weighting adjustments for the National Comorbidity Survey (1990–1992), a large-scale national epidemiologic investigation of the prevalence, risk factors, and consequences of psychiatric morbidity and comorbidity in the United States. Weighting adjustments for differential selection within households, new construction, unit nonresponse, and poststratification were examined separately and in combination. Specific issues addressed included the magnitude of the bias incurred from ignoring the weights, the added variance from weighting and how well this was predicted by simple formulae, and the performance of methods for trimming the weights. Weights had quite modest effects on point estimates of prevalences but resulted in major increases in variance unless trimmed. The weights after trimming and poststratification appeared to work well. It is suggested that the added variance from weighting be carefully monitored in similar surveys. Alternatives to the use of trimming for controlling variance are worth exploring.

Trimming

A-weighting

10.1093/oxfordjournals.aje.a009297

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Citations (72)

Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial

Gut (2012)

Wolfgang Hueber Bruce E. Sands Steve Lewitzky Marc Vandemeulebroecke Walter Reinisch

Objective

The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn9s disease.

Design

In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn9s disease (Crohn9s Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response.

Results

59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected).

Conclusions

Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo.

Clinical trial registration

This trial was registered at ClinicalTrial.gov with the number NCT01009281.

Clinical endpoint

10.1136/gutjnl-2011-301668

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Citations (1,377)

Acknowledgement to the Reviewers

Human Heredity (2003)

Jeanette McCarthy Steve Lewitzky Cynthia Reeves Alan Permutt Benjamin Glaser

Acknowledgement

10.1159/000074396

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Citations (0)

OC-036 A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury

Gut (2010)

Charles Paulding Jonathan B. Singer Steve Lewitzky E Leroy Feng Zhao

Introduction Lumiracoxib is a selective COX-2 inhibitor that was developed for the symptomatic treatment of osteoarthritis and acute pain. Concerns over liver injury, primarily at chronic doses >100 mg once daily, led to the withdrawal of lumiracoxib in most major drug markets worldwide. A genome-wide association study was performed to identify genetic markers associated with lumiracoxib-related liver injury. Methods Using DNA (n=10 057) collected during the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), a multistaged case-control pharmacogenetic study was conducted to identify genetic markers associated with the risk of developing elevations of liver aminotransferases (ALT/AST) during treatment with lumiracoxib. TARGET was a 52-week, gastrointestinal clinical safety outcomes study which demonstrated that lumiracoxib (400 mg once daily) reduced the risk of a definite or probable upper GI ulcer complication by 79% compared to NSAIDs (naproxen 500 mg twice daily and ibuprofen 800 mg three times daily) in non-aspirin treated osteoarthritis patients. Results Several single nucleotide polymorphisms (SNPs) from the MHC class II region on chromosome 6 were found to be associated with liver aminotransferase elevations five times the upper limit of normal (>5×ULN) in patients treated with lumiracoxib (top SNP p=2.8E-10). These findings were replicated in an independent set of patients with elevated aminotransferases (>3×ULN) (top SNP p=4.4E-12). To further refine the association results, HLA genotyping and analysis were conducted and a very strong association was identified (top HLA allele p=6.8E-25). Conclusion The study described here identified a highly significant association between HLA alleles and lumiracoxib-related liver injury. These results offer the potential to improve the safety profile of lumiracoxib by excluding patients at elevated risk for developing liver injury.

10.1136/gut.2009.208959j

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Citations (1)

A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

The American Journal of Human Genetics (2001)

Xin Xu Zhian Fang Binyan Wang Changzhong Chen Wenwei Guang

Methacholine

Vital capacity

Linkage (software)

Genetic linkage

10.1086/324650

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Citations (105)

SR-B1 variants associated with HDL cholesterol levels in three populations

The American Journal of Human Genetics (2001)

Jeanette McCarthy Steve Lewitzky Alan Permutt Benjamin Gläser Leif Groop

Source

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Citations (3)

Erratum: A gene conferring susceptibility to type 2 diabetes in conjunction with obesty is located on chromosme 18p11 (Diabetes (2001) 50 (675-680))

Diabetes (2001)

Alexander N. Parker J Meyer Steve Lewitzky Jean S. Rennich Gabriel Chan

Conjunction (astronomy)

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Subsampling Callbacks to Improve Survey Efficiency

Journal of the American Statistical Association (2000)

Michael R. Elliott Roderick J. A. Little Steve Lewitzky

Abstract Abstract The National Comorbidity Survey (NCS), a 1990–1992 nationwide face-to-face survey of the U.S. population age 15–54 regarding the prevalence of psychiatric comorbidity, required, as with most large-scale surveys, multiple callbacks to maximize response rates. As a consequence, it appeared that a substantial proportion of the data collection cost came from the many callbacks required to obtain a small proportion of interviews with difficult-to-reach respondents. Thus we were led to explore whether the efficiency of data collection could be increased by subsampling a random proportion α of the originally sampled units from the mth callback attempt forward, with case weights used to remove bias. Similar considerations led the designers of the American Community Survey (ACS) to subsample households in the face-to-face portion of a three-mode postal, telephone, and face-to-face survey. In this article we determine the expected cost of a given interview under two strategies—subsampling versus no subsampling—as a function of the probability of obtaining an interview at the kth callback, the cost of the kth callback, and the cost of an interview or cost of a refusal if obtained at the kth callback. We then determine the sample size required to maintain a constant variance of a mean estimated under the two sampling strategies. We give an efficiency ratio as the ratio of the total costs under the two sampling strategies. This ratio is minimized as a function of m (the callback on which subsampling begins) and α (the proportion of sampling units retained) under the assumed cost and probability-of-interview structure. We then show that subsampling becomes a potentially efficient strategy whenever (a) the per callback or per interview cost is increasing and (b) the probability of a successful interview attempt is decreasing. Although these conditions are routinely met in sample surveys, it appears that they must be met to a substantial degree for useful savings to occur. In the case of the NCS, we found that only trivial savings could be achieved. Although unfortunate in one sense, this finding is useful in proving that a strategy that seemed intuitively reasonable offers only very modest practical benefit. Subsampling in the ACS seems to be more cost-effective; however, our analysis suggests that subsampling should begin at the telephone rather than the face-to-face mode. Key Words: Survey design

Callback

Sample (material)

10.2307/2669453

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Citations (3)

Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population

Proceedings of the National Academy of Sciences (2001)

L. Alison McInnes Susan K. Service Victor I. Reus Glenn Barnes Olga Charlat

We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.

Pedigree chart

Linkage Disequilibrium

Population stratification

Candidate gene

Genetic linkage

10.1073/pnas.191519098

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Citations (38)