Publications by authors named "Jill Hardin"

20 Publications

  • Page 1 of 1

Medications for attention-deficit/hyperactivity disorder in Japan: A retrospective cohort study of label compliance.

Neuropsychopharmacol Rep 2021 Jun 28. Epub 2021 Jun 28.

Department of Epidemiology, Janssen Research & Development, LLC, Titusville, NJ, USA.

Aim: To assess label compliance in prescription of medications approved for treatment of attention-deficit/hyperactivity disorder (ADHD) in Japan at the time of this study: methylphenidate (MPH), atomoxetine, and guanfacine.

Methods: Retrospective descriptive study was conducted in prevalent-user cohorts from the Japan Medical Data Center database. Patients who were prescribed a study drug between January 1, 2013 and September 30, 2018 and were in the database for ≥30 days were included. A prescription was considered compliant if all 4 criteria were satisfied: appropriate age, daily dose not exceeding the approved maximum, no contraindicated concurrent medications, and no contraindicated conditions.

Results: Among 17 418 patients who were prescribed a study drug during 2013-2018, 73% were male and 53% were children (aged <18 years). Fewer than 2% of prescriptions were for patients outside the approved age, 10%-13% of patients in the atomoxetine and MPH cohorts received ≥1 prescription exceeding maximum approved dose, no patients were co-prescribed a contraindicated medication, and 16%-18% of patients in the MPH cohorts had ≥1 contraindicated condition. During their first 500 days of use, for approximately 73%-86% of patients, all prescriptions were compliant with all label requirements.

Conclusions: Among patients exposed to ADHD medications in Japan during 2013-2018, nearly all prescriptions for these medications were label-compliant for age. For >85% of patients, all prescriptions were label-compliant for dose, and for approximately 80%, all prescriptions were label-compliant for contraindicated conditions. We did not find evidence of widespread abuse or noncompliant use of prescribed ADHD medications.
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http://dx.doi.org/10.1002/npr2.12191DOI Listing
June 2021

Understanding patient journey in ulcerative colitis prior to biologic initiation: a 5-year exploration.

BMC Gastroenterol 2021 Mar 17;21(1):121. Epub 2021 Mar 17.

Janssen Global Services, LLC, Raritan, 08869, NJ, USA.

Background: There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn's disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent.

Methods: UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients' treatment, disease progression and overall health care utilization prior to initiating biologic agents.

Results: Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased.

Conclusions: Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.
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http://dx.doi.org/10.1186/s12876-021-01708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967955PMC
March 2021

Understanding patient journey in ulcerative colitis prior to biologic initiation: a 5-year exploration.

BMC Gastroenterol 2021 Mar 17;21(1):121. Epub 2021 Mar 17.

Janssen Global Services, LLC, Raritan, 08869, NJ, USA.

Background: There has been a more pronounced shift toward earlier, more aggressive therapies in Crohn's disease than in ulcerative colitis (UC). The aim of this study was to describe the pre-biologic treatment and health care experience, including co-morbidities and overall health care utilization, for UC patients who initiated biologic therapies, in the 5 years prior to the initiation of the first biologic agent.

Methods: UC patients who initiated a biologic agent approved for UC between 9/15/2005 and 1/30/2018 were identified from the IBM® MarketScan® Commercial Database, a large US database. The date of the first recorded UC biologic exposure was defined as the index date, and ≥ 5 years of pre-index records were required to evaluate patients' treatment, disease progression and overall health care utilization prior to initiating biologic agents.

Results: Among the 1891 eligible patients, treatment with oral corticosteroids, 5-aminosalicylates, and other non-biologic immunomodulators, all increased progressively across the 5 years prior to the index. From within year-five to within year-one prior to the index, the median duration of oral corticosteroid treatment increased from 34 to 88 days per year and the proportion of patients who experienced more extensive/pancolitis disease increased from 16 to 59%. Overall, the frequency of all-cause health care visits also increased.

Conclusions: Patients with UC experienced increasing morbidity and treatment burden in the 5 years prior to initiating biologic therapy. To achieve reduced corticosteroids in UC management, better risk stratification is needed to help identify patients for more timely biologic treatment.
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http://dx.doi.org/10.1186/s12876-021-01708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967955PMC
March 2021

Deep phenotyping of 34,128 adult patients hospitalised with COVID-19 in an international network study.

Nat Commun 2020 10 6;11(1):5009. Epub 2020 Oct 6.

Clinical Pharmacology Unit, Zealand University Hospital, Køge, Denmark.

Comorbid conditions appear to be common among individuals hospitalised with coronavirus disease 2019 (COVID-19) but estimates of prevalence vary and little is known about the prior medication use of patients. Here, we describe the characteristics of adults hospitalised with COVID-19 and compare them with influenza patients. We include 34,128 (US: 8362, South Korea: 7341, Spain: 18,425) COVID-19 patients, summarising between 4811 and 11,643 unique aggregate characteristics. COVID-19 patients have been majority male in the US and Spain, but predominantly female in South Korea. Age profiles vary across data sources. Compared to 84,585 individuals hospitalised with influenza in 2014-19, COVID-19 patients have more typically been male, younger, and with fewer comorbidities and lower medication use. While protecting groups vulnerable to influenza is likely a useful starting point in the response to COVID-19, strategies will likely need to be broadened to reflect the particular characteristics of individuals being hospitalised with COVID-19.
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http://dx.doi.org/10.1038/s41467-020-18849-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538555PMC
October 2020

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study.

Lancet Rheumatol 2020 Nov 21;2(11):e698-e711. Epub 2020 Aug 21.

Janssen Research and Development, Titusville, NJ, USA.

Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis.

Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the value was less than 0·4.

Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12-2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22-3·95]), chest pain or angina (1·15 [1·05-1·26]), and heart failure (1·22 [1·02-1·45]).

Interpretation: Hydroxychloroquine treatment appears to have no increased risk in the short term among patients with rheumatoid arthritis, but in the long term it appears to be associated with excess cardiovascular mortality. The addition of azithromycin increases the risk of heart failure and cardiovascular mortality even in the short term. We call for careful consideration of the benefit-risk trade-off when counselling those on hydroxychloroquine treatment.

Funding: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre, NIHR Senior Research Fellowship programme, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research and Development, IQVIA, Korea Health Industry Development Institute through the Ministry of Health and Welfare Republic of Korea, Versus Arthritis, UK Medical Research Council Doctoral Training Partnership, Foundation Alfonso Martin Escudero, Innovation Fund Denmark, Novo Nordisk Foundation, Singapore Ministry of Health's National Medical Research Council Open Fund Large Collaborative Grant, VINCI, Innovative Medicines Initiative 2 Joint Undertaking, EU's Horizon 2020 research and innovation programme, and European Federation of Pharmaceutical Industries and Associations.
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http://dx.doi.org/10.1016/S2665-9913(20)30276-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442425PMC
November 2020

An international characterisation of patients hospitalised with COVID-19 and a comparison with those previously hospitalised with influenza.

medRxiv 2020 Apr 25. Epub 2020 Apr 25.

Background: To better understand the profile of individuals with severe coronavirus disease 2019 (COVID-19), we characterised individuals hospitalised with COVID-19 and compared them to individuals previously hospitalised with influenza.

Methods: We report the characteristics (demographics, prior conditions and medication use) of patients hospitalised with COVID-19 between December 2019 and April 2020 in the US (Columbia University Irving Medical Center [CUIMC], STAnford Medicine Research data Repository [STARR-OMOP], and the Department of Veterans Affairs [VA OMOP]) and Health Insurance Review & Assessment [HIRA] of South Korea. Patients hospitalised with COVID-19 were compared with patients previously hospitalised with influenza in 2014-19.

Results: 6,806 (US: 1,634, South Korea: 5,172) individuals hospitalised with COVID-19 were included. Patients in the US were majority male (VA OMOP: 94%, STARR-OMOP: 57%, CUIMC: 52%), but were majority female in HIRA (56%). Age profiles varied across data sources. Prevalence of asthma ranged from 7% to 14%, diabetes from 18% to 43%, and hypertensive disorder from 22% to 70% across data sources, while between 9% and 39% were taking drugs acting on the renin-angiotensin system in the 30 days prior to their hospitalisation. Compared to 52,422 individuals hospitalised with influenza, patients admitted with COVID-19 were more likely male, younger, and, in the US, had fewer comorbidities and lower medication use.

Conclusions: Rates of comorbidities and medication use are high among individuals hospitalised with COVID-19. However, COVID-19 patients are more likely to be male and appear to be younger and, in the US, generally healthier than those typically admitted with influenza.
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http://dx.doi.org/10.1101/2020.04.22.20074336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239064PMC
April 2020

Liver Test Monitoring: Real-World Compliance for Drugs with Monitoring Requirements at 2-Week Intervals or More Frequently.

Pharmaceut Med 2019 10;33(5):389-394

Janssen Pharmaceutical Research and Development, LLC, 1125 Trenton-Harbourton Rd., Titusville, NJ, 08560, USA.

Background: Monitoring risk is often an important component of therapy. Some compounds require liver test (LT) monitoring, with the frequency detailed in the product label. Compliance with these instructions is generally unknown.

Objective: The goal of this short study was to describe LT compliance for compounds with monitoring recommended at 2-week intervals or more frequently in three US administrative claims databases.

Methods: The sample was drawn from three US claims databases during the period 1 January 2015 through 30 June 2018. This study examined nine compounds and five types of LTs. We looked at compounds in a published list of drugs requiring LTs at 2-week intervals or more frequently. Descriptive statistics about the days between tests were reported, as were the number and proportion of tests associated with each drug that met the recommended frequency.

Results: Compliance was < 33% with four drugs (ketoconazole, succimer, pentamidine, and felbamate) and > 60% with five drugs (oxaliplatin, rifampin, tolcapone, albendazole, and azathioprine). Among drugs with more than 1000 drug eras observed (all but succimer and tolcapone), LT compliance was highest for oxaliplatin (75.3%) and lowest for pentamidine (20.6%), with little difference in overall compliance by type of test (range 41-46).

Conclusion: Compliance with frequent LT monitoring differed for the drugs examined. Two strata were found: compliance > 60% (oxaliplatin, rifampin, tolcapone, albendazole, and azathioprine) and compliance 20-30% (ketoconazole, succimer, pentamidine, and felbamate). No drug reached 80% compliance.
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http://dx.doi.org/10.1007/s40290-019-00294-zDOI Listing
October 2019

Criteria2Query: a natural language interface to clinical databases for cohort definition.

J Am Med Inform Assoc 2019 04;26(4):294-305

Department of Biomedical Informatics, Columbia University, New York, New York, USA.

Objective: Cohort definition is a bottleneck for conducting clinical research and depends on subjective decisions by domain experts. Data-driven cohort definition is appealing but requires substantial knowledge of terminologies and clinical data models. Criteria2Query is a natural language interface that facilitates human-computer collaboration for cohort definition and execution using clinical databases.

Materials And Methods: Criteria2Query uses a hybrid information extraction pipeline combining machine learning and rule-based methods to systematically parse eligibility criteria text, transforms it first into a structured criteria representation and next into sharable and executable clinical data queries represented as SQL queries conforming to the OMOP Common Data Model. Users can interactively review, refine, and execute queries in the ATLAS web application. To test effectiveness, we evaluated 125 criteria across different disease domains from ClinicalTrials.gov and 52 user-entered criteria. We evaluated F1 score and accuracy against 2 domain experts and calculated the average computation time for fully automated query formulation. We conducted an anonymous survey evaluating usability.

Results: Criteria2Query achieved 0.795 and 0.805 F1 score for entity recognition and relation extraction, respectively. Accuracies for negation detection, logic detection, entity normalization, and attribute normalization were 0.984, 0.864, 0.514 and 0.793, respectively. Fully automatic query formulation took 1.22 seconds/criterion. More than 80% (11+ of 13) of users would use Criteria2Query in their future cohort definition tasks.

Conclusions: We contribute a novel natural language interface to clinical databases. It is open source and supports fully automated and interactive modes for autonomous data-driven cohort definition by researchers with minimal human effort. We demonstrate its promising user friendliness and usability.
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http://dx.doi.org/10.1093/jamia/ocy178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402359PMC
April 2019

Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.

Behav Genet 2016 Mar 21;46(2):151-69. Epub 2015 Sep 21.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.

The mu1 opioid receptor gene, OPRM1, has long been a high-priority candidate for human genetic studies of addiction. Because of its potential functional significance, the non-synonymous variant rs1799971 (A118G, Asn40Asp) in OPRM1 has been extensively studied, yet its role in addiction has remained unclear, with conflicting association findings. To resolve the question of what effect, if any, rs1799971 has on substance dependence risk, we conducted collaborative meta-analyses of 25 datasets with over 28,000 European-ancestry subjects. We investigated non-specific risk for "general" substance dependence, comparing cases dependent on any substance to controls who were non-dependent on all assessed substances. We also examined five specific substance dependence diagnoses: DSM-IV alcohol, opioid, cannabis, and cocaine dependence, and nicotine dependence defined by the proxy of heavy/light smoking (cigarettes-per-day >20 vs. ≤ 10). The G allele showed a modest protective effect on general substance dependence (OR = 0.90, 95% C.I. [0.83-0.97], p value = 0.0095, N = 16,908). We observed similar effects for each individual substance, although these were not statistically significant, likely because of reduced sample sizes. We conclude that rs1799971 contributes to mechanisms of addiction liability that are shared across different addictive substances. This project highlights the benefits of examining addictive behaviors collectively and the power of collaborative data sharing and meta-analyses.
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http://dx.doi.org/10.1007/s10519-015-9737-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752855PMC
March 2016

A genetic signature of spina bifida risk from pathway-informed comprehensive gene-variant analysis.

PLoS One 2011 30;6(11):e28408. Epub 2011 Nov 30.

Department of Molecular and Cellular Biology, California Institute for Quantitative Biosciences, University of California, Berkeley, California, United States of America.

Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028408PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3227667PMC
April 2012

Impact of meat consumption, preparation, and mutagens on aggressive prostate cancer.

PLoS One 2011 23;6(11):e27711. Epub 2011 Nov 23.

Department of Urology, University of California San Francisco, San Francisco, California, United States of America.

Background: The association between meat consumption and prostate cancer remains unclear, perhaps reflecting heterogeneity in the types of tumors studied and the method of meat preparation--which can impact the production of carcinogens.

Methods: We address both issues in this case-control study focused on aggressive prostate cancer (470 cases and 512 controls), where men reported not only their meat intake but also their meat preparation and doneness level on a semi-quantitative food-frequency questionnaire. Associations between overall and grilled meat consumption, doneness level, ensuing carcinogens and aggressive prostate cancer were assessed using multivariate logistic regression.

Results: Higher consumption of any ground beef or processed meats were positively associated with aggressive prostate cancer, with ground beef showing the strongest association (OR = 2.30, 95% CI:1.39-3.81; P-trend = 0.002). This association primarily reflected intake of grilled or barbequed meat, with more well-done meat conferring a higher risk of aggressive prostate cancer. Comparing high and low consumptions of well/very well cooked ground beef to no consumption gave OR's of 2.04 (95% CI:1.41-2.96) and 1.51 (95% CI:1.06-2.14), respectively. In contrast, consumption of rare/medium cooked ground beef was not associated with aggressive prostate cancer. Looking at meat mutagens produced by cooking at high temperatures, we detected an increased risk with 2-amino-3,8-Dimethylimidazo-[4,5-f]Quinolaxine (MelQx) and 2-amino-3,4,8-trimethylimidazo(4,5-f)qunioxaline (DiMelQx), when comparing the highest to lowest quartiles of intake: OR = 1.69 (95% CI:1.08-2.64;P-trend = 0.02) and OR = 1.53 (95% CI:1.00-2.35; P-trend = 0.005), respectively.

Discussion: Higher intake of well-done grilled or barbequed red meat and ensuing carcinogens could increase the risk of aggressive prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0027711PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223211PMC
April 2012

Impact of consumption of vegetable, fruit, grain, and high glycemic index foods on aggressive prostate cancer risk.

Nutr Cancer 2011 20;63(6):860-72. Epub 2011 Jul 20.

Department of Epidemiology, University of California at San Francisco, San Francisco, California 94158-9001, USA.

Prostate cancer is a common but complex disease, and distinguishing modifiable risk factors such as diet for more aggressive disease is extremely important. Previous work has detected intriguing associations between vegetable, fruit, and grains and more aggressive prostate cancer, although these remain somewhat unclear. Here we further investigate such potential relationships with a case-control study of 982 men (470 more aggressive prostate cancer cases and 512 control subjects). Comparing the highest to lowest quartiles of intake, we found that increasing intakes of leafy vegetables were inversely associated with risk of aggressive prostate cancer [adjusted odds ratio (OR) = 0.66, 95% CI: 0.46, 0.96; P trend = 0.02], as was higher consumption of high carotenoid vegetables (OR = 0.71, 95% CI: 0.48, 1.04; P trend = 0.04). Conversely, increased consumption of high glycemic index foods were positively associated with risk of aggressive disease (OR = 1.64, 95% CI: 1.05, 2.57; P trend = 0.02). These results were driven by a number of specific foods within the food groups. Our findings support the hypothesis that diets high in vegetables and low in high glycemic index foods decrease risk of aggressive prostate cancer.
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http://dx.doi.org/10.1080/01635581.2011.582224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209415PMC
December 2011

Non-Steroidal Anti-Inflammatory Drugs, Variation in Inflammatory Genes, and Aggressive Prostate Cancer.

Pharmaceuticals (Basel) 2010 Oct;3(10):3127-3142

Department of Urology, University of California at San Francisco, 1450 3 Street, San Francisco, CA 94158, USA.

Increasing evidence suggests that prostatic inflammation plays a key role in the development of prostate cancer. It remains controversial whether non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of prostate cancer. Here, we investigate how a previously reported inverse association between NSAID use and the risk of aggressive prostate cancer is modulated by variants in several inflammatory genes. We found that NSAIDs may have differential effects on prostate cancer development, depending on one's genetic makeup. Further study of these inflammatory pathways may clarify the mechanisms through which NSAIDs impact prostate cancer risk.
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http://dx.doi.org/10.3390/ph3103127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3766748PMC
October 2010

Resequencing of nicotinic acetylcholine receptor genes and association of common and rare variants with the Fagerström test for nicotine dependence.

Neuropsychopharmacology 2010 Nov 25;35(12):2392-402. Epub 2010 Aug 25.

Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA.

Common single-nucleotide polymorphisms (SNPs) at nicotinic acetylcholine receptor (nAChR) subunit genes have previously been associated with measures of nicotine dependence. We investigated the contribution of common SNPs and rare single-nucleotide variants (SNVs) in nAChR genes to Fagerström test for nicotine dependence (FTND) scores in treatment-seeking smokers. Exons of 10 genes were resequenced with next-generation sequencing technology in 448 European-American participants of a smoking cessation trial, and CHRNB2 and CHRNA4 were resequenced by Sanger technology to improve sequence coverage. A total of 214 SNP/SNVs were identified, of which 19.2% were excluded from analyses because of reduced completion rate, 73.9% had minor allele frequencies <5%, and 48.1% were novel relative to dbSNP build 129. We tested associations of 173 SNP/SNVs with the FTND score using data obtained from 430 individuals (18 were excluded because of reduced completion rate) using linear regression for common, the cohort allelic sum test and the weighted sum statistic for rare, and the multivariate distance matrix regression method for both common and rare SNP/SNVs. Association testing with common SNPs with adjustment for correlated tests within each gene identified a significant association with two CHRNB2 SNPs, eg, the minor allele of rs2072660 increased the mean FTND score by 0.6 Units (P=0.01). We observed a significant evidence for association with the FTND score of common and rare SNP/SNVs at CHRNA5 and CHRNB2, and of rare SNVs at CHRNA4. Both common and/or rare SNP/SNVs from multiple nAChR subunit genes are associated with the FTND score in this sample of treatment-seeking smokers.
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http://dx.doi.org/10.1038/npp.2010.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055324PMC
November 2010

Longitudinal genetic analysis of brain volumes in normal elderly male twins.

Neurobiol Aging 2012 Apr 13;33(4):636-44. Epub 2010 Jul 13.

Center for Health Sciences, SRI International, Menlo Park, CA, USA.

This study investigated the role of genetic and environmental influences on individual differences in brain volumes measured at 2 time points in normal elderly males from the National Heart, Lung, and Blood Institute Twin Study. The magnetic resonance imaging (MRI) scans were conducted 4 years apart on 33 monozygotic and 33 dizygotic male twin pairs, aged 68 to 77 years when first scanned. Volumetric measures of total brain and total cerebrospinal fluid were significantly heritable at baseline (over 70%). For both volumes genetic influences at follow-up were entirely accounted for by genetic influences at baseline, suggesting that the same genetic factors influence variability in brain volume at each time of assessment. Variability in 4-year volume change was due to shared and individual-specific environmental influences. There was little evidence for heritable influences on change measures. These results suggest that variation in longitudinal change of some brain volume measures may have different underlying genetic and environmental architecture from variation in repeat cross-sectional measures, which could have implications for intervention strategies for age-related illness associated with brain morphology. The results of this study are discussed in the context of the small sample size and associated limitations of statistical power.
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http://dx.doi.org/10.1016/j.neurobiolaging.2010.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970700PMC
April 2012

Nicotine withdrawal sensitivity, linkage to chr6q26, and association of OPRM1 SNPs in the SMOking in FAMilies (SMOFAM) sample.

Cancer Epidemiol Biomarkers Prev 2009 Dec;18(12):3399-406

SRI International, Menlo Park, CA 94025, USA.

Background: Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms.

Methods: The objectives of these analyses were to (a) assess the influence of nicotine withdrawal sensitivity on relapse, (b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and (c) explore family-based association of single nucleotide polymorphism (SNP) at the mu opioid receptor candidate gene (OPRM1) with nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores.

Results: An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, 1.25; 95% confidence interval, 1.10-1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family-based association test with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P values <0.05 and false discovery rate Q values <0.06.

Conclusion: An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs were found with Rasch-modeled nicotine withdrawal sensitivity scores in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.
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http://dx.doi.org/10.1158/1055-9965.EPI-09-0960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536862PMC
December 2009

Whole genome microarray analysis, from neonatal blood cards.

BMC Genet 2009 Jul 22;10:38. Epub 2009 Jul 22.

University of California Berkeley, School of Public Health, Berkeley, CA 94720, USA.

Background: Neonatal blood, obtained from a heel stick and stored dry on paper cards, has been the standard for birth defects screening for 50 years. Such dried blood samples are used, primarily, for analysis of small-molecule analytes. More recently, the DNA complement of such dried blood cards has been used for targeted genetic testing, such as for single nucleotide polymorphism in cystic fibrosis. Expansion of such testing to include polygenic traits, and perhaps whole genome scanning, has been discussed as a formal possibility. However, until now the amount of DNA that might be obtained from such dried blood cards has been limiting, due to inefficient DNA recovery technology.

Results: A new technology is employed for efficient DNA release from a standard neonatal blood card. Using standard Guthrie cards, stored an average of ten years post-collection, about 1/40th of the air-dried neonatal blood specimen (two 3 mm punches) was processed to obtain DNA that was sufficient in mass and quality for direct use in microarray-based whole genome scanning. Using that same DNA release technology, it is also shown that approximately 1/250th of the original purified DNA (about 1 ng) could be subjected to whole genome amplification, thus yielding an additional microgram of amplified DNA product. That amplified DNA product was then used in microarray analysis and yielded statistical concordance of 99% or greater to the primary, unamplified DNA sample.

Conclusion: Together, these data suggest that DNA obtained from less than 10% of a standard neonatal blood specimen, stored dry for several years on a Guthrie card, can support a program of genome-wide neonatal genetic testing.
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http://dx.doi.org/10.1186/1471-2156-10-38DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2722673PMC
July 2009

Simple and inexpensive point-of-care tests improve diagnosis of vaginal infections in resource constrained settings.

Trop Med Int Health 2009 Jun 20;14(6):703-8. Epub 2009 Apr 20.

San Francisco Department of Public Health, San Francisco, CA 94103, USA.

Objective: Bacterial vaginosis (BV) and Trichomonas vaginalis infection (TV) have been associated with adverse birth outcomes and increased risk for HIV. We compare the performance of simple inexpensive point-of-care (POC) tests to laboratory diagnosis and syndromic management of BV and TV in poor settings.

Methods: Between November 2005 and March 2006, 898 sexually active women attending two reproductive health clinics in Mysore, India were recruited into a cohort study investigating the relationship between vaginal flora and HSV-2 infection. Participants were interviewed and screened for reproductive tract infections. Laboratory tests included serology for HSV-2; cultures for TV, Candida sp., and Neisseria gonorrhoeae; Gram stains; and two POC tests: vaginal pH; and Whiff test.

Results: Of the 898 participants, 411 [45.7%, 95% confidence interval (95% CI): 42.4-49.0%] had any laboratory diagnosed vaginal infection. BV was detected in 165 women (19.1%, 95%CI: 16.5-21.9%) using Nugent score. TV was detected in 76 women (8.5%, 95%CI: 6.7-10.4%) using culture. Among the entire study population, POC correctly detected 82% of laboratory diagnosed BV cases, and 83% of laboratory diagnosed TV infections. Among women with complaints of vulval itching, burning, abnormal vaginal discharge, and/or sores (445/898), POC correctly detected 83% (60 of 72 cases) of laboratory diagnosed BV cases vs. 40% (29 of 72 cases) correctly managed using the syndromic approach (P < 0.001). Similarly, POC would have detected 82% (37 of 45 cases) of TV cases vs. 51% (23 of 45 cases) correctly managed using the syndromic approach (P = 0.001).

Conclusions: In the absence of laboratory diagnostics, POC is not only inexpensive and practical, but also significantly more sensitive than the syndromic management approach, resulting in less overtreatment. .
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http://dx.doi.org/10.1111/j.1365-3156.2009.02274.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625926PMC
June 2009

Trends in the probability of twins and males in California, 1983-2003.

Twin Res Hum Genet 2009 Feb;12(1):93-102

March of Dimes, California Research Division, Children's Hospital Oakland Research Institute, Oakland, California 94609, United States of America.

This study examines the probability of twins by birth year, maternal race-ethnicity, age, and parity and the influences of these demographic factors on the probability of male in twins and singletons in a large, racially diverse population. Recent publications note steep increases in twin births while the probability of male births has been reported to vary by parental race-ethnicity and age and birth order. Probability of male stratified by plurality has not been investigated in California prior to this study. Cubic spline estimates and Poisson regression techniques were employed to describe trends in twins and males using California vital statistics birth and fetal death records over the period from 1983-2003. This study includes 127,787 twin pair and 11,025,106 singleton births. The probability of twins varied by birth year, maternal race-ethnicity, age, and parity. The probability of twins increased by 10.1% from 1983-1992 and increased by 20.1% from 1993-2003, nearly doubling the previous increase. All maternal race-ethnicity groups showed increases in probability of twins with increasing maternal age. Parous women compared to nulliparous women had larger increases in the probability of twins. The probability of males in twins decreased from 1983-1992 and increased from 1993-2003; while in singletons the probability appeared unchanged. These findings show increases in the probability of twins in California from 1983-2003 and identify maternal age, race-ethnicity, and parity groups most likely to conceive twins. The cause of the increase in twins is unknown but coincides with trends towards delayed childbearing and increased use of subfertility treatments.
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http://dx.doi.org/10.1375/twin.12.1.93DOI Listing
February 2009

The estimated probability of dizygotic twins: a comparison of two methods.

Twin Res Hum Genet 2009 Feb;12(1):79-85

March of Dimes, California Research Division, Children's Hospital Oakland Research Institute, Oakland, California 94609, United States of America.

This study presents a general model of two binary variables and applies it to twin sex pairing data from 21 twin data sources to estimate the frequency of dizygotic twins. The purpose of this study is to clarify the relationship between maximum likelihood and Weinberg's differential rule zygosity estimation methods. We explore the accuracy of these zygosity estimation measures in relation to twin ascertainment methods and the probability of a male. Twin sex pairing data from 21 twin data sources representing 15 countries was collected for use in this study. Maximum likelihood estimation of the probability of dizygotic twins is applied to describe the variation in the frequency of dizygotic twin births. The differences between maximum likelihood and Weinberg's differential rule zygosity estimation methods are presented as a function of twin data ascertainment method and the probability of a male. Maximum likelihood estimation of the probability of dizygotic twins ranges from 0.083 (95% approximate CI: 0.082, 0.085) to 0.750 (95% approximate CI: 0.749, 0.752) for voluntary ascertainment data sources and from 0.374 (95% approximate CI: 0.373, 0.375) to 0.987 (95% approximate CI: 0.959, 1.016) for active ascertainment data sources. In 17 of the 21 twin data sources differences of 0.01 or less occur between maximum likelihood and Weinberg zygosity estimation methods. The Weinberg and maximum likelihood estimates are negligibly different in most applications. Using the above general maximum likelihood estimate, the probability of a dizygotic twin is subject to substantial variation that is largely a function of twin data ascertainment method.
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http://dx.doi.org/10.1375/twin.12.1.79DOI Listing
February 2009