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Biomedical subjects

Keith Humphreys

Publications and source records attributed to Keith Humphreys.

At least 19 recordsLinked to original sources
PubMed2006

Linkage disequilibrium mapping of CHEK2: common variation and breast cancer risk.

BACKGROUND: Checkpoint kinase 2 (CHEK2) averts cancer development by promoting cell cycle arrest and activating DNA repair in genetically damaged cells. Previous investigation has established a role for the CHEK2 gene in breast cancer aetiology, but studies have largely been limited to the rare 1100delC mutation. Whether common polymorphisms in this gene influence breast cancer risk remains unknown. In this study, we aimed to assess the importance of common CHEK2 variants on population risk for breast cancer by capturing the majority of diversity in the gene using haplotype tagging single nucleotide polymorphisms (tagSNPs). METHODS AND FINDINGS: We analyzed 14 common SNPs spanning 52 kilobases (kb) of the CHEK2 gene in 92 Swedish women. Coverage evaluation indicated that these typed SNPs would efficiently convey association signal also from untyped SNPs in the same region. Six of the 14 SNPs predicted well both the haplotypic and single SNP variations within CHEK2. We genotyped these six tagSNPs in 1,577 postmenopausal breast cancer cases and 1,513 population controls, but found no convincing association between any common CHEK2 haplotype and breast cancer risk. The 1100delC mutation was rare in our Swedish population--0.7% in cases and 0.4% in controls--with a corresponding odds ratio for carriers versus noncarriers of 2.26 (95% confidence interval, 0.99-5.15). Estimates of the population frequency and the odds ratio of 1100delC indicate that our sample is representative of a Northern European population. CONCLUSIONS: Notwithstanding the involvement of the CHEK2 gene in breast cancer aetiology, we show that common polymorphisms do not influence postmenopausal breast cancer risk.

Aged↗
PubMed2006

Variation in DNA repair genes ERCC2, XRCC1, and XRCC3 and risk of follicular lymphoma.

The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common susceptibility involving suboptimal DNA repair. Therefore, we investigated selected polymorphisms and haplotypes in three DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in the ERCC2, XRCC1, and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of three SNPs [Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5)]. These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1, may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.

Adolescent↗
PubMed2006

Determining effective methadone doses for individual opioid-dependent patients.

BACKGROUND: Randomized clinical trials of methadone maintenance have found that on average high daily doses are more effective for reducing heroin use, and clinical practice guidelines recommend 60 mg/d as a minimum dosage. Nevertheless, many clinicians report that some patients can be stably maintained on lower methadone dosages to optimal effect, and clinic dosing practices vary substantially. Studies of individual responses to methadone treatment may be more easily translated into clinical practice. METHODS AND FINDINGS: A volunteer sample of 222 opioid-dependent US veterans initiating methadone treatment was prospectively observed over the year after treatment entry. In the 168 who achieved at least 1 mo of heroin abstinence, methadone dosages on which patients maintained heroin-free urine samples ranged from 1.5 mg to 191.2 mg (median = 69 mg). Among patients who achieved heroin abstinence, higher methadone dosages were predicted by having a diagnosis of posttraumatic stress disorder or depression, having a greater number of previous opioid detoxifications, living in a region with lower average heroin purity, attending a clinic where counselors discourage dosage reductions, and staying in treatment longer. These factors predicted 42% of the variance in dosage associated with heroin abstinence. CONCLUSIONS: Effective and ineffective methadone dosages overlap substantially. Dosing guidelines should focus more heavily on appropriate processes of dosage determination rather than solely specifying recommended dosages. To optimize therapy, methadone dosages must be titrated until heroin abstinence is achieved.

Adult↗
PubMed2006

Opioid substitution treatment reduces substance use equivalently in patients with and without posttraumatic stress disorder.

OBJECTIVE: The purpose of this study was to determine whether opioid-dependent patients with diagnosed posttraumatic stress disorder (PTSD) have poorer long-term outcomes in opioid substitution treatment than do patients without PTSD. METHOD: This prospective observational study examined outcomes of 255 opioid-dependent patients (men = 248) entering opioid substitution treatment at eight clinics in the Veterans Health Administration (VHA). Subjects were interviewed at treatment entry, 6 months, and 1 year about substance use and related problems, health status, treatment satisfaction, and non-VHA health care utilization. Medical records were reviewed to obtain toxicology results, health care utilization data, and diagnoses. Medical record review identified a diagnosis of PTSD in 71 (28%) patients. Substance-use and mental-health outcomes and health care utilization in the first year following treatment entry were compared between patients with and without a diagnosis of PTSD. RESULTS: Patients with and without PTSD had similar treatment responses. Although patients with PTSD had longer histories of drug use at intake, at 1-year follow-up they showed reductions in heroin, cocaine, and alcohol use, comparable to patients without the disorder. PTSD patients received higher doses of opiate medication, attended more psychosocial treatment sessions for substance-use disorder, and had better treatment retention. Psychiatric symptoms for patients with PTSD were more severe at intake and showed little improvement throughout treatment. CONCLUSIONS: Opioid substitution therapy is as effective at reducing substance use in PTSD patients as it is in patients without the disorder, but additional services are needed for treatment of psychological problems that are largely unchanged by treatment for addiction.

Adult↗
PubMed2005

Fine-scale mapping in case-control samples using locus scoring and haplotype-sharing methods.

Both haplotype-based and locus-based methods have been proposed as the most powerful methods to employ when fine mapping by association. Although haplotype-based methods utilize more information, they may lose power as a result of overparameterization, given the large number of haplotypes possible over even a few loci. Recently methods have been developed that cluster haplotypes with similar structure in the hope that this reflects shared genealogical ancestry. The aim is to reduce the number of parameters while retaining the genotype information relating to disease susceptibility. We have compared several haplotype-based methods with locus-based methods. We utilized 2 regions (D2 and D4) simulated to be in linkage disequilibrium and to be associated with disease susceptibility, combining 5 replicates at a time to produce 4 datasets that were analyzed. We found little difference in the performance of the haplotype-based methods and the locus-based methods in this dataset.

Case-Control Studies↗
PubMed2005

Analysis of binary traits: testing association in the presence of linkage.

Most methods for testing association in the presence of linkage, using family-based studies, have been developed for continuous traits. FBAT (family-based association tests) is one of few methods appropriate for discrete outcomes. In this article we describe a new test of association in the presence of linkage for binary traits. We use a gamma random effects model in which association and linkage are modelled as fixed effects and random effects, respectively. We have compared the gamma random effects model to an FBAT and a generalized estimating equation-based alternative, using two regions in the Genetic Analysis Workshop 14 simulated data. One of these regions contained haplotypes associated with disease, and the other did not.

Genetic Linkage↗
PubMed2005

Predictors of retention in methadone programs: a signal detection analysis.

Retention in Opioid Agonist Therapy (OAT) is associated with reductions in substance use, HIV risk behavior, and criminal activities in opioid dependent patients. To improve the effectiveness of treatment for opioid dependence, it is important to identify predisposing characteristics and provider-related variables that predict retention in OAT. Participants include 258 veterans enrolled in 8 outpatient methadone/l-alpha-acetylmethadol (LAAM) treatment programs. Signal detection analysis was utilized to identify variables predictive of 1-year retention and to identify the optimal cut-offs for significant predictors. Provider-related variables play a vital role in predicting retention in OAT programs, as higher methadone dose (> or =59 mg/day) and greater treatment satisfaction were among the strongest predictors of retention at 1-year follow-up.

Adult↗
PubMed2005

Response to methadone maintenance treatment of opiate dependent patients with and without significant pain.

BACKGROUND: Both clinicians and researchers have expressed doubt that opiate dependent patients with significant pain can be effectively treated in methadone maintenance treatment (MMT) programs; however, little research exists on this topic. Patients who report significant pain in the month preceding entry to MMT present with a distinct and more severe pattern of polysubstance use, medical and psychosocial problems than do those without pain. The present study investigated the 1-year treatment outcomes of MMT patients with opiate dependence and pain. METHODS: Analyses were based on a national sample of 200 patients presenting in MMT programs for treatment of opiate dependence. Substance use and related problems were measured at treatment entry and 12 months later. Patients reported pain severity over the month preceding treatment entry. RESULTS: Compared to patients without significant pain, patients who reported significant pain at baseline (n = 103) showed similar substance-related functioning, but poorer psychosocial functioning at 1 year. CONCLUSIONS: Patients with and without significant pain experience comparable reductions in substance use when provided with standard care in MMT programs. However, additional medical and/or mental health treatment is needed for their pain and other problems.

Adult↗
PubMed2005

CYP17 gene polymorphism in relation to breast cancer risk: a case-control study.

INTRODUCTION: The c.1-34T>C 5' promoter region polymorphism in cytochrome P450c17 (CYP17), a key enzyme in the biosynthesis of estrogen, has been associated with breast cancer risk, but most previous studies have been relatively small. METHODS: We genotyped 1,544 incident cases of primary breast cancer and 1,502 population controls, all postmenopausal Swedish women, for the CYP17 c.1-34T>C polymorphism and calculated odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression models. RESULTS: No overall association was found between CYP17 c.1-34T>C and breast cancer risk, OR 1.0 (95% CI 0.8-1.3) for the A2/A2 (CC) carriers compared to the A1/A1 (TT) carriers, regardless of histopathology. We detected an interaction between CYP17 c.1-34T>C and age at menarche (P = 0.026) but regarded that as a chance finding as no dose-response pattern was evident. Other breast cancer risk factors, including menopausal hormone use and diabetes mellitus, did not modify the overall results. CONCLUSION: It is unlikely that CYP17 c.1-34T>C has a role in breast cancer etiology, overall or in combination with established non-genetic breast cancer risk factors.

Aged↗
PubMed2005

Prevention of peer rejection through a classroom-level intervention in middle school.

This project evaluated an intervention for preventing peer rejection in middle school that promoted social acceptance in the classroom environment. The systems-level and preventive focus of this intervention differed markedly from traditional interventions that target putative deficits within individual rejected children. In collaboration with 24 teachers and their classrooms, the intervention team led mixed groups of accepted and rejected children in cooperative games that required teamwork and mutual respect among all members in order to succeed. To reinforce these alliances between children, as well as to prevent future peer rejection, teachers were encouraged to use cooperative, teamwork-based group activities for academic instruction. The intervention was evaluated using a randomized control (waitlist) design. Results suggested that the intervention reduced the amount of self-reported peer rejection in classrooms. Implications for the further development and evaluation of systems-level interventions to prevent peer rejection are discussed. EDITORS' STRATEGIC IMPLICATIONS: The use of a systems-based prevention program shows promise for the prevention of children's perceived peer rejection. The authors demonstrate a model of university-community collaboration with a plan for sustainability and a focus on low-income and minority populations. Educators, school administrators, and researchers will be intrigued by the positive experiences of non-rejected peers and teachers in promoting a socially accepting school climate.

Adolescent↗
PubMed2005

Internet and paper self-help materials for problem drinking: is there an additive effect?

The objective of this study was to conduct a preliminary evaluation of an Internet-based intervention for problem drinkers, comparing changes in drinking between respondents who only received the intervention to those who also received a self-help book. After receiving a personalized feedback summary on the Internet, 83 respondents provided complete baseline information and volunteered to participate in a 3-month follow-up survey. Half of the respondents were randomized to receive an additional self-help book. The follow-up was returned by 48 respondents (69% female). Repeated measures ANOVAs were conducted to compare drinking levels at baseline and 3-month follow-up among respondents who only received the Internet-based intervention. There was minimal support for an impact of the Internet intervention alone. In addition, hierarchical regression analyses were conducted to compare respondents in the two intervention conditions on their drinking at follow-up, controlling for baseline consumption. Respondents who received the additional self-help book reported drinking less and experiencing fewer consequences at follow-up as compared to respondents who received only the Internet-based intervention. While the results are promising, they cannot be taken as evidence of the efficacy of Internet-based personalized feedback as a stand-alone intervention because of the absence of a control group that did not receive the intervention. Further research on this topic should be a priority because of the potential for Internet-based interventions to reach problem drinkers underserved by traditional treatment.

Adult↗
PubMed2005

Prevalence and predictors of research participant eligibility criteria in alcohol treatment outcome studies, 1970-98.

AIMS: To describe the eligibility criteria (i.e. study participant inclusion and exclusion rules) employed in alcohol treatment outcome research and to identify predictors of their use. DESIGN: The eligibility criteria of 683 alcohol treatment outcome studies conducted between 1970 and 1998 were coded reliably into 14 general categories. Predictors of the use of eligibility criteria were then examined. FINDINGS: Patients were most often ruled ineligible for research studies because of their level of alcohol problems (39.1% of studies), comorbid psychiatric problems (37.8%), past or concurrent utilization of alcohol treatment (31.8%), co-occurring medical conditions (31.6%), and because they were deemed non-compliant and unmotivated (31.5%). The number of eligibility criteria employed in studies increased from the 1970s through the 1990s, and was positively associated with funding from the US National Institute of Alcohol Abuse and Alcoholism (NIAAA) and from the private sector, lack of an inpatient/residential treatment condition, presence of a pharmacotherapy, and use of a randomized, multiple-condition design. Principal investigators with doctoral degrees used more eligibility criteria than those with lower degrees. CONCLUSION: Participant eligibility criteria are extensively employed in alcohol treatment outcome research, and vary significantly across historical periods, funders and research designs. Researchers should report the details of subject eligibility criteria and excluded patients more fully, and, evaluate how eligibility criteria affect the cost, feasibility, and generalizability of treatment outcome research.

Alcoholism↗
PubMed2005

Validity and reliability of the German version of the short understanding of substance abuse scale.

This paper presents the German version of the Short Understanding of Substance Abuse Scale (SUSS) [Humphreys et al.: Psychol Addict Behav 1996;10:38-44], the Verstandnis von Storungen durch Substanzkonsum (VSS), and evaluates its psychometric properties. The VSS assesses clinicians' beliefs about the nature and treatment of substance use disorders, particularly their endorsement of psychosocial and disease orientation. The VSS was administered to 160 treatment staff members at 12 substance use disorder treatment programs in the German-speaking part of Switzerland. Because the confirmatory factor analysis of the VSS did not completely replicate the factorial structure of the SUSS, an exploratory factor analysis was undertaken. This analysis identified two factors: the Psychosocial model factor and a slightly different Disease model factor. The VSS Disease and Psychosocial subscales showed convergent and discriminant validity, as well as sufficient reliability.

Adult↗
PubMed2004

Oestrogen receptor alpha gene haplotype and postmenopausal breast cancer risk: a case control study.

INTRODUCTION: Oestrogen receptor alpha, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor alpha gene (ESR1) are associated with breast cancer risk. METHODS: We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TAn, 1514 cases and 1514 controls; c.454-397C --> T, 1557 cases and 1512 controls; c.454-351A --> G, 1556 cases and 1512 controls; c.729C --> T, 1562 cases and 1513 controls; c.975C --> G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. RESULTS: There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A --> G or c.454-397C --> T and c.975C --> G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A --> G and c.975C --> G haplotype entailed an OR of 1.19 (95% CI 1.06-1.33) and two copies with an OR of 1.42 (95% CI 1.15-1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C --> T and c.975C --> G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. CONCLUSION: We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women.

Aged↗
PubMed2004

Treatment needs associated with pain in substance use disorder patients: implications for concurrent treatment.

Although pain problems are prevalent in substance use disorder (SUD) patients, the special treatment needs of SUD patients with pain have not been investigated. This study examines the problems and behaviors associated with reported pain among veterans treated at eight opioid substitution treatment clinics. Patients reporting pain had more severe medical and psychiatric problems and greater health care utilization. Pain was associated with an increased propensity for misuse of substances with analgesic effects, suggesting that ongoing pain contributes to an altered and more severe pattern of drug-seeking behavior. Patients without pain rarely abused sedatives or opioid medication, indicating that misuse of these substances is unique to co-morbid pain and SUD patients. Patients reporting pain did not differ from patients without pain in use of heroin, alcohol, cocaine or in injection practices, demonstrating that they are truly SUD patients in need of SUD treatment. Pain complicates the treatment of SUD and should be addressed as an important co-morbidity during treatment.

Adult↗