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1.  Predictors of consent to pharmacogenomics testing in the IDEAL study 
Pharmacogenetics and genomics  2013;23(11):619-623.
Pharmacogenomic (PG) testing is important in developing individualized therapeutic approaches. In the phase 3 IDEAL clinical trial, a subset of patients receiving peginterferon and ribavirin for treatment of chronic hepatitis C agreed to provide blood samples for genetic testing. Genome-wide association studies subsequently identified associations between IL28B polymorphism and sustained virologic response, and ITPA polymorphism and ribavirin-associated anemia.
To characterize the groups of patients who accepted or declined PG testing in the IDEAL study.
Clinical and demographic factors and treatment outcomes were compared at all sites that had approved PG testing. Differences between patients who consented to and declined PG testing were analyzed using Student t and chi-square tests.
In total, 109 of 118 sites participated in the PG sub-study, and 1674 of 2949 (57%) patients enrolled at these sites consented to PG testing. More patients treated in academic medical centers than in community centers (60% vs. 52%, P < 0.001) provided consent. More males than females (58% vs. 54%, P = 0.04) consented to PG testing. There was no significant difference in PG participation between patients from different racial groups, including whites and African Americans (58% vs. 54%, P = 0.07). Treatment outcomes were also similar according to PG participation.
In the IDEAL study, patient consent to PG testing did not introduce selection bias. Treatment at an academic center and male gender were associated with higher rates of PG testing consent. Efficacy and safety outcomes were similar in patients who accepted and declined PG testing.
PMCID: PMC3951733  PMID: 24061202
pharmacogenomics; hepatitis C; peginterferon; ribavirin
2.  Racial Differences in Hepatitis C Treatment Eligibility 
Hepatology (Baltimore, Md.)  2011;54(1):70-78.
Black Americans are disproportionally infected with hepatitis C virus (HCV) and are less likely than whites to respond to treatment with peginterferon (PEG-IFN) plus ribavirin (RBV). The impact of race on HCV treatment eligibility is unknown. We therefore performed a retrospective analysis of a phase 3B multicenter clinical trial conducted at 118 United States community and academic medical centers to evaluate the rates of and reasons for HCV treatment ineligibility according to self-reported race. In all, 4,469 patients were screened, of whom 1,038 (23.2%) were treatment ineligible. Although blacks represented 19% of treated patients, they were more likely not to be treated due to ineligibility and/or failure to complete required evaluations (40.2%) than were nonblack patients (28.5%; P < 0.001). After the exclusion of persons not treated due to undetectable HCV RNA or nongenotype 1 infection, blacks were 65% less likely than nonblacks to be eligible for treatment (28.1% > 17.0%; relative risk, 1.65; 95% confidence interval, 1.46–1.87; P< 0.001). Blacks were more likely to be ineligible due to neutropenia (14% versus 3%, P < 0.001), anemia (7% versus 4%, P = 0.02), elevated glucose (8% versus 3%, P < 0.001), and elevated creatinine (5% versus 1%, P < 0.001).
Largely due to a higher prevalence of neutropenia and uncontrolled medical conditions, blacks were significantly less likely to be eligible for HCV treatment. Increased access to treatment may be facilitated by less conservative neutrophil requirements and more effective care for chronic diseases, namely, diabetes and renal insufficiency.
PMCID: PMC3736356  PMID: 21488082
3.  Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients 
Journal of hepatology  2011;56(2):313-319.
Background & Aims
Interferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (peg-IFN)-related thrombocytopenia, neutropenia, and leukopenia.
1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80 × 109/L and an absolute neutrophil count (ANC) ≥ 1500/mm3. Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n = 1294).
6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p = 10−10). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p = 10−12, p = 10−7) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r = −0.28, p = 10−17) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.
Two ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.
PMCID: PMC3634361  PMID: 21703177
GWAS; ITPA; Thrombocytopenia; Hepatitis C; Neutropenia; IL28B
4.  Association of a Polymorphism in the Indoleamine-2,3-Dioxygenase Gene and Interferon-α-Induced Depression in Patients with Chronic Hepatitis C 
Molecular Psychiatry  2011;17(8):781-789.
Interferon (IFN)-α treatment for infectious diseases and cancer is associated with significant depressive symptoms that can limit therapeutic efficacy. Multiple mechanisms have been implicated in IFN-α-induced depression including immune, neuroendocrine and neurotransmitter pathways. To further explore mechanisms of IFN-α-induced depression and establish associated genetic risk factors, single nucleotide polymorphisms in genes encoding proteins previously implicated in IFN-α-induced depression were explored in 2 self-reported ethnic groups, Caucasians (n=800) and African Americans (n=232), participating in a clinical trial on the impact of three pegylated IFN-α treatment regimens on sustained viral response in patients with chronic hepatitis C. Prior to treatment, all subjects were free of psychotropic medications and had a score ≤20 on the Center for Epidemiologic Studies Depression Scale (CES-D), which was used to assess depressive symptom severity throughout the study. In Caucasians, a polymorphism (rs9657182) in the promoter region of the gene encoding indoleamine-2,3-dioxygenase (IDO1) was found to be associated with moderate or severe IFN-α-induced depressive symptoms (CES-D >20) at 12 weeks of IFN-α treatment (p=0.0012, p<0.05 corrected). Similar results were obtained for treatment weeks 24, 36 and 48. In subjects homozygous for the risk allele (CC, n=150), the odds ratio for developing moderate or severe depressive symptoms at treatment week 12 was 2.91 (CI: 1.48–5.73) compared to TT homozygotes (n=270). rs9657182 did not predict depression in African Americans, who exhibited a markedly lower frequency of the risk allele at this locus. The findings in Caucasians further support the notion that indoleamine-2,3-dioxygenase plays an important role in cytokine-induced behavioral changes.
PMCID: PMC3179823  PMID: 21691274
interferon-α; indoleamine-2; 3-dioxygenase; cytokines; depression; genes; single nucleotide polymorphism
5.  The Association of Genetic Variants with Hepatic Steatosis in Patients with Genotype 1 Chronic Hepatitis C Infection 
Digestive diseases and sciences  2012;57(8):2213-2221.
Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.
We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.
A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3). Multivariable analysis tested IL28B and PNPLA3 for association with the presence of any steatosis (>0 %); clinically significant steatosis (>5 %); steatosis severity (grade 0–3/4); and the interacting associations of the SNPs and hepatic steatosis to sustained viral response (SVR).
IL28B and PNPLA3 polymorphisms were associated with the presence of any steatosis (rs12979860, p = 1.87 × 10−7; rs2896019, p = 7.56 × 10−4); clinically significant steatosis (rs12979860, p = 1.82 × 10−3; rs2896019, p = 1.27 × 10−4); and steatosis severity (rs12979860, p = 2.05 × 10−8; rs2896019, p = 2.62 × 10−6). Obesity, hypertriglyceridemia, hyperglycemia, liver fibrosis, and liver inflammation were all independently associated with worse steatosis. Hepatic steatosis was associated with lower SVR, and this effect was attenuated by IL28B. PNPLA3 had no independent association with SVR.
IL28B and PNPLA3 are associated with hepatic steatosis prevalence and severity in Caucasians with G1 HCV, suggesting differing potential genetic risk pathways to steatosis. IL28B attenuates the association between steatosis and SVR. Remediable metabolic risk factors remain important, independently of these polymorphisms, and remain key therapeutic goals to achieve better outcomes for patients with HCV-associated hepatic steatosis.
PMCID: PMC3518927  PMID: 22543885
Polymorphism, single-nucleotide, SNP; IL28B protein, human; PNPLA3 protein, human; Adiponutrin, human; Fatty liver; Abdominal obesity metabolic syndrome
6.  Laboratory-acquired Brucellosis 
Emerging Infectious Diseases  2004;10(10):1848-1850.
We report two laboratory-acquired Brucella melitensis infections that were shown to be epidemiologically related. Blood culture isolates were initially misidentified because of variable Gram stain results, which led to misdiagnoses and subsequent laboratory exposures. Notifying laboratory personnel who unknowingly processed cultures from brucellosis patients is an important preventive measure.
PMCID: PMC3323255  PMID: 15504276
brucellosis; laboratory-acquired; Gram stain; dispatch
7.  Bioterrorism-related Inhalational Anthrax in an Elderly Woman, Connecticut, 2001 
Emerging Infectious Diseases  2003;9(6):681-688.
On November 20, 2001, inhalational anthrax was confirmed in an elderly woman from rural Connecticut. To determine her exposure source, we conducted an extensive epidemiologic, environmental, and laboratory investigation. Molecular subtyping showed that her isolate was indistinguishable from isolates associated with intentionally contaminated letters. No samples from her home or community yielded Bacillus anthracis, and she received no first-class letters from facilities known to have processed intentionally contaminated letters. Environmental sampling in the regional Connecticut postal facility yielded B. anthracis spores from 4 (31%) of 13 sorting machines. One extensively contaminated machine primarily processes bulk mail. A second machine that does final sorting of bulk mail for her zip code yielded B. anthracis on the column of bins for her carrier route. The evidence suggests she was exposed through a cross-contaminated bulk mail letter. Such cross-contamination of letters and postal facilities has implications for managing the response to future B. anthracis–contaminated mailings.
PMCID: PMC3000148  PMID: 12781007
Bacillus anthracis; inhalational anthrax; bioterrorism; postal facilities; research
8.  Anthrax Postexposure Prophylaxis in Postal Workers, Connecticut, 2001 
Emerging Infectious Diseases  2002;8(10):1133-1137.
After inhalational anthrax was diagnosed in a Connecticut woman on November 20, 2001, postexposure prophylaxis was recommended for postal workers at the regional mail facility serving the patient’s area. Although environmental testing at the facility yielded negative results, subsequent testing confirmed the presence of Bacillus anthracis. We distributed questionnaires to 100 randomly selected postal workers within 20 days of initial prophylaxis. Ninety-four workers obtained antibiotics, 68 of whom started postexposure prophylaxis and 21 discontinued. Postal workers who stopped or never started taking prophylaxis cited as reasons disbelief regarding anthrax exposure, problems with adverse events, and initial reports of negative cultures. Postal workers with adverse events reported predominant symptoms of gastrointestinal distress and headache. The influence of these concerns on adherence suggests that communication about risks of acquiring anthrax, education about adverse events, and careful management of adverse events are essential elements in increasing adherence.
PMCID: PMC2730305  PMID: 12396928
Anthrax; Bacillus anthracis; prophylaxis; adverse effects; ciprofloxacin; doxycycline; patient noncompliance; Connecticut

Results 1-8 (8)