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PubMed2005

Extension of multifactor dimensionality reduction for identifying multilocus effects in the GAW14 simulated data.

The multifactor dimensionality reduction (MDR) is a model-free approach that can identify gene x gene or gene x environment effects in a case-control study. Here we explore several modifications of the MDR method. We extended MDR to provide model selection without crossvalidation, and use a chi-square statistic as an alternative to prediction error (PE). We also modified the permutation test to provide different levels of stringency. The extended MDR (EMDR) includes three permutation tests (fixed, non-fixed, and omnibus) to obtain p-values of multilocus models. The goal of this study was to compare the different approaches implemented in the EMDR method and evaluate the ability to identify genetic effects in the Genetic Analysis Workshop 14 simulated data. We used three replicates from the simulated family data, generating matched pairs from family triads. The results showed: 1) chi-square and PE statistics give nearly consistent results; 2) results of EMDR without cross-validation matched that of EMDR with 10-fold cross-validation; 3) the fixed permutation test reports false-positive results in data from loci unrelated to the disease, but the non-fixed and omnibus permutation tests perform well in preventing false positives, with the omnibus test being the most conservative. We conclude that the non-cross-validation test can provide accurate results with the advantage of high efficiency compared to 10-cross-validation, and the non-fixed permutation test provides a good compromise between power and false-positive rate.

Computer Simulation↗
PubMed2005

The effect of missing data on linkage disequilibrium mapping and haplotype association analysis in the GAW14 simulated datasets.

We used our newly developed linkage disequilibrium (LD) plotting software, JLIN, to plot linkage disequilibrium between pairs of single-nucleotide polymorphisms (SNPs) for three chromosomes of the Genetic Analysis Workshop 14 Aipotu simulated population to assess the effect of missing data on LD calculations. Our haplotype analysis program, SIMHAP, was used to assess the effect of missing data on haplotype-phenotype association. Genotype data was removed at random, at levels of 1%, 5%, and 10%, and the LD calculations and haplotype association results for these levels of missingness were compared to those for the complete dataset. It was concluded that ignoring individuals with missing data substantially affects the number of regions of LD detected which, in turn, could affect tagging SNPs chosen to generate haplotypes.

Chromosome Mapping↗
PubMed2005

Linkage mapping of a complex trait in the New York population of the GAW14 simulated dataset: a multivariate phenotype approach.

Multivariate phenotypes underlie complex traits. Thus, instead of using the end-point trait, it may be statistically more powerful to use a multivariate phenotype correlated to the end-point trait for detecting linkage. In this study, we develop a reverse regression method to analyze linkage of Kofendrerd Personality Disorder affection status in the New York population of the Genetic Analysis Workshop 14 (GAW14) simulated dataset. When we used the multivariate phenotype, we obtained significant evidence of linkage near four of the six putative loci in at least 25% of the replicates. On the other hand, the linkage analysis based on Kofendrerd Personality Disorder status as a phenotype produced significant findings only near two of the loci and in a smaller proportion of replicates.

Chromosome Mapping↗
PubMed2005

Construction of the model for the Genetic Analysis Workshop 14 simulated data: genotype-phenotype relationships, gene interaction, linkage, association, disequilibrium, and ascertainment effects for a complex phenotype.

The Genetic Analysis Workshop 14 simulated dataset was designed 1) To test the ability to find genes related to a complex disease (such as alcoholism). Such a disease may be given a variety of definitions by different investigators, have associated endophenotypes that are common in the general population, and is likely to be not one disease but a heterogeneous collection of clinically similar, but genetically distinct, entities. 2) To observe the effect on genetic analysis and gene discovery of a complex set of gene x gene interactions. 3) To allow comparison of microsatellite vs. large-scale single-nucleotide polymorphism (SNP) data. 4) To allow testing of association to identify the disease gene and the effect of moderate marker x marker linkage disequilibrium. 5) To observe the effect of different ascertainment/disease definition schemes on the analysis. Data was distributed in two forms. Data distributed to participants contained about 1,000 SNPs and 400 microsatellite markers. Internet-obtainable data consisted of a finer 10,000 SNP map, which also contained data on controls. While disease characteristics and parameters were constant, four "studies" used varying ascertainment schemes based on differing beliefs about disease characteristics. One of the studies contained multiplex two- and three-generation pedigrees with at least four affected members. The simulated disease was a psychiatric condition with many associated behaviors (endophenotypes), almost all of which were genetic in origin. The underlying disease model contained four major genes and two modifier genes. The four major genes interacted with each other to produce three different phenotypes, which were themselves heterogeneous. The population parameters were calibrated so that the major genes could be discovered by linkage analysis in most datasets. The association evidence was more difficult to calibrate but was designed to find statistically significant association in 50% of datasets. We also simulated some marker x marker linkage disequilibrium around some of the genes and also in areas without disease genes. We tried two different methods to simulate the linkage disequilibrium.

Computer Simulation↗
PubMed2005

Linkage analysis of GAW14 simulated data: comparison of multimarker, multipoint, and conditional approaches.

The purposes of this study were 1) to examine the performance of a new multimarker regression approach for model-free linkage analysis in comparison to a conventional multipoint approach, and 2) to determine the whether a conditioning strategy would improve the performance of the conventional multipoint method when applied to data from two interacting loci. Linkage analysis of the Kofendrerd Personality Disorder phenotype to chromosomes 1 and 3 was performed in three populations for all 100 replicates of the Genetic Analysis Workshop 14 simulated data. Three approaches were used: a conventional multipoint analysis using the Zlr statistic as calculated in the program ALLEGRO; a conditioning approach in which the per-family contribution on one chromosome was weighted according to evidence for linkage on the other chromosome; and a novel multimarker regression approach. The multipoint and multimarker approaches were generally successful in localizing known susceptibility loci on chromosomes 1 and 3, and were found to give broadly similar results. No advantage was found with the per-family conditioning approach. The effect on power and type I error of different choices of weighting scheme (to account for different numbers of affected siblings) in the multimarker approach was examined.

Chromosome Mapping↗
PubMed2005

Genome-wide linkage and association mapping of disease genes with the GAW14 simulated datasets.

We combined the results of whole-genome linkage and association analyses to determine which markers were most strongly associated with Kofendrerd Personality Disorder. Using replicate 1 from the Genetic Analysis Workshop 14 Aipotu, Karangar, Danacaa, and New York City simulated populations, we determined that several markers showed significant linkage and association with disease status. We used both SNP and microsatellite markers to determine patterns and chromosomal regions of markers. Three consistently associated markers were C01R0050, C03R0280, and C10R0882. Using generalized linear mixed models, we modelled the effect of the three predefined phenotypic categories on disease status and concluded that the phenotypes defining the "anxiety-related" category best predicted the outcome.

Chromosome Mapping↗
PubMed2005

Covariate linkage analysis of GAW14 simulated data incorporating subclinical phenotype, sex, population, parent-of-origin, and interaction.

BACKGROUND: We evaluate a method for the incorporation of covariates into linkage analysis using the Genetic Analysis Workshop 14 simulated data. Focusing on a randomly chosen replicate (42) we investigated the effect of the 12 subclinical phenotypes, sex, population, and parent-of-origin on the linkage signal from a model-free linkage analysis of Kofendrerd Personality Disorder. RESULTS: We detected a linkage peak on chromosome 1, at about 175 cM, which varied depending upon individuals' status for subclinical phenotype b. A linkage peak on chromosome 3 (310 cM) was found not to depend upon subclinical phenotype status. Further peaks were found on chromosomes 5 (12 cM), 9 (4 cM), and 10 (95 cM), depending on the status of subclinical phenotypes a, k, and c/d/g, respectively. CONCLUSION: Retrospective comparison of our results with the simulation model showed correct identification of disease loci D1-5 on chromosomes 1, 3, 5, 9 and 10, respectively.

Chromosome Mapping↗
PubMed2005

Identification of polymorphisms explaining a linkage signal: application to the GAW14 simulated data.

We applied three approaches for the identification of polymorphisms explaining the linkage evidence to the Genetic Analysis Workshop 14 simulated data: 1) the genotype-IBD sharing test (GIST); 2) an approach suggested by Horikawa and colleagues; and 3) the homozygote sharing test (HST). These tests were compared with a family-based association test. Two linked regions with highest nonparametric linkage scores were selected to apply these methods. In the first region, Horikawa's method identified the most SNPs within the region containing the disease susceptibility locus, while HST performed best in the second region. However, Horikawa's method also had the most type I errors. These methods show potential as additional tools to complement family-based association tests for the identification of disease susceptibility variants.

Chromosomes, Human, Pair 1↗
PubMed2003

More insight into the fate of biomedical meeting abstracts: a systematic review.

BACKGROUND: It has been estimated that about 45% of abstracts that are accepted for presentation at biomedical meetings will subsequently be published in full. The acceptance of abstracts at meetings and their fate after initial rejection are less well understood. We set out to estimate the proportion of abstracts submitted to meetings that are eventually published as full reports, and to explore factors that are associated with meeting acceptance and successful publication. METHODS: Studies analysing acceptance of abstracts at biomedical meetings or their subsequent full publication were searched in MEDLINE, OLDMEDLINE, EMBASE, Cochrane Library, CINAHL, BIOSIS, Science Citation Index Expanded, and by hand searching of bibliographies and proceedings. We estimated rates of abstract acceptance and of subsequent full publication, and identified abstract and meeting characteristics associated with acceptance and publication, using logistic regression analysis, survival-type analysis, and meta-analysis. RESULTS: Analysed meetings were held between 1957 and 1999. Of 14945 abstracts that were submitted to 43 meetings, 46% were accepted. The rate of full publication was studied with 19123 abstracts that were presented at 234 meetings. Using survival-type analysis, we estimated that 27% were published after two, 41% after four, and 44% after six years. Of 2412 abstracts that were rejected at 24 meetings, 27% were published despite rejection. Factors associated with both abstract acceptance and subsequent publication were basic science and positive study outcome. Large meetings and those held outside the US were more likely to accept abstracts. Abstracts were more likely to be published subsequently if presented either orally, at small meetings, or at a US meeting. Abstract acceptance itself was strongly associated with full publication. CONCLUSIONS: About one third of abstracts submitted to biomedical meetings were published as full reports. Acceptance at meetings and publication were associated with specific characteristics of abstracts and meetings.

Biomedical Research↗
PubMed2005

A unified web-based query and notification system (QNS) for subject management, adverse events, regulatory, and IRB components of clinical trials.

Even after intensive review, interpretative questions, ambiguities, contradictions, or errors, will arise once the protocol is scrutinized by site IRBs and implemented at sites. This will occur despite preparation and implementation of site protocol training, and provision of well crafted case report forms for the reporting of clinical and laboratory evaluations and adverse events. Since many staff are involved in each protocol, site investigators or study coordinators might direct protocol queries, participant management, or IRB queries to different network participants, resulting in inconsistent responses. It is important to establish a response mechanism that ensures consistent responses and their systematic documentation. For reporting of adverse events, and the submission of or documentation of completion of regulatory requirements, an easily accessible and structured communications system is also required. This paper describes the development and implementation of a user-friendly web-based query and notification system (QNS) for subject management, adverse events, regulatory, and IRB components. This system was created in the Adolescent Trials Network for HIV/AIDS Interventions (ATN), using existing web based tools with minor modifications and minimal cost. The query and notification system is interactive and allows for free flow of information among the site coordinators and both the protocol teams and the regulatory group. The process of the system is transparent to users at the sites, although its use and maintenance is controlled by Data Operations Center staff, to assure that ATN requirements for review and approval are met. This results in consistency of and timeliness of responses to queries, timeliness and accuracy of adverse event reporting and the ability for the data operations center regulatory staff to provide notification of pending or delinquent regulatory submissions.

Adolescent↗
PubMed1994

Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: an Illinois Cancer Center study.

PURPOSE: Past research that has compared cancer treatment tolerance between elderly and nonelderly cancer patients has been contradictory. Some investigators concluded that there is no difference between the groups, while others demonstrated elderly patients experienced less tolerance to treatment. As a result, some physicians discriminate against elderly cancer patients by not entering them onto clinical trials out of a belief that they will not tolerate the therapy. METHODS: An analysis was performed using the Illinois Cancer Center (ICC) data base, which contains treatment information for all patients registered onto phase II trials. A maximum of 672 cases was available for evaluation of 11 treatment-related variables. RESULTS: The results demonstrated no significant differences between elderly and nonelderly patients for the following seven treatment-related variables: performance status (PS), number of dose reductions, number of treatment interruptions, total days of delay, best response, reason off-study, and number of grade 3 or greater toxicities. Minor differences were detected for number of courses and number of dose escalations. CONCLUSION: Based on these results, elderly patients should not be denied access to cancer clinical trials relative to age alone.

Aged↗
PubMed2002

Opioid dependence treatment, including buprenorphine/naloxone.

OBJECTIVE: To review opioid dependence (OD) and its treatment. Pharmacologic treatments, including the use of buprenorphine/naloxone, are presented. Pharmaceutical care functions for outpatient OD treatment are discussed. DATA SOURCES: Primary and review articles were identified by MEDLINE and HEALTHSTAR searches (from 1966 to November 2000) and through secondary sources. Tertiary sources were also reviewed regarding general concepts of OD and its treatment. STUDY SELECTION/DATA EXTRACTION: Relevant articles were reviewed after identification from published abstracts. Articles were selected based on the objectives for this article. Studies of the treatment of OD with buprenorphine were selected based on the topic (pharmacology, pharmacokinetics, adverse reactions) and study design (randomized, controlled clinical trials in patients with OD with active/placebo comparisons and/or comparisons of active OD treatments). Articles regarding pharmacists' activities in the treatment and prevention of OD were reviewed for the pharmaceutical care section. DATA SYNTHESIS: OD is considered a medical disorder with costly adverse health outcomes. Although methadone maintenance treatment (MMT) is cost-effective for OD, only about 12% of individuals with OD receive this treatment. Psychological and pharmacologic modalities are used to treat OD, but patients often relapse. Drug therapy includes alpha 2-agonists for withdrawal symptoms, detoxification regimens with or without opioids, opioid antagonists, and opioid replacement including methadone, levomethadyl acetate, and buprenorphine. The Drug Addiction Treatment Act of 1999 allows for office-based opioid replacement therapies. Sublingual buprenorphine with naloxone can be used in this milieu. Buprenorphine with naloxone is currently under new drug application review with the Food and Drug Administration. Clinical research shows buprenorphine to be equal in effectiveness to methadone, but safer in overdose due to its ceiling effect on respiratory depression. It has lower abuse potential and fewer withdrawal symptoms when discontinued. Naloxone is included to decrease diversion and injection of the tablets. Pharmacists in outpatient settings who are familiar with OD have opportunities to provide pharmaceutical care to patients receiving this treatment. Pharmaceutical care functions for OD include ensuring appropriate drug administration, monitoring adverse effects, alleviating withdrawal symptoms, treating intercurrent illnesses, minimizing diversion, and preventing relapse. CONCLUSIONS: OD is a critical unmet health problem in the US. Buprenorphine combined with naloxone represents an innovative treatment for OD in outpatient settings. This new treatment has advantages over MMT.

Administration, Sublingual↗
PubMed2002

Secretin for the treatment of autism.

OBJECTIVE: To evaluate the role of secretin in the treatment of children with autism. DATA SOURCE: Literature was assessed through MEDLINE, EMBASE, BIOSIS (November 1998-August 2001), and the World Wide Web. Literature included scientific studies, anecdotal reports, and meeting abstracts. Key search terms included autism and secretin. DATA SYNTHESIS: Autism is a pervasive developmental disorder. Although several treatments exist, no cure has been identified. New information suggests that secretin may be beneficial for this disorder. A critical evaluation of current information about the use of secretin in autism was conducted. CONCLUSIONS: Currently, several anecdotal reports and a few controlled trials with conflicting results have been published regarding the use of secretin in autism. Further studies should be conducted to determine the safety and efficacy of secretin for autism.

Adolescent↗
PubMed2000

Cefdinir: an expanded-spectrum oral cephalosporin.

OBJECTIVE: To review the antimicrobial activity, pharmacokinetics, clinical efficacy, and tolerability of cefdinir, an expanded-spectrum oral cephalosporin. DATA SOURCES: Literature was identified by a MEDLINE search (January 1983-November 1999) of the medical literature, review of English-language literature and bibliographies of these articles, and product information. STUDY SELECTION: Clinical efficacy data were selected from all published trials mentioning cefdinir. Additional information concerning in vitro susceptibility, safety, chemistry, and pharmacokinetic profile of cefdinir was also reviewed. DATA SYNTHESIS: Cefdinir, an oral expanded-spectrum cephalosporin, has a broad spectrum of activity against many gram-negative and -positive aerobic organisms, including Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefdinir is stable to hydrolysis by many common beta-lactamases. Cefdinir is rapidly absorbed from the gastrointestinal tract and is primarily eliminated via renal clearance of unchanged drug. The terminal disposition half-life of cefdinir is approximately 1.5 hours. Efficacy has been demonstrated in a number of clinical trials in adults and children with upper and lower respiratory tract infections (e.g., pharyngitis, sinusitis, acute otitis media, acute bronchitis, acute exacerbation of chronic bronchitis, community-acquired pneumonia) and skin and skin-structure infections. The adverse event profile is similar to that of comparator agents. CONCLUSIONS: Cefdinir is a second-line alternative to first-line antimicrobial agents, with convenient once- or twice-daily dosing in the treatment of upper and lower respiratory tract infections and skin and skin-structure infections. Similar to other oral expanded-spectrum cephalosporins, cefdinir has activity against common pathogens of the respiratory tract and skin and is stable in the presence of many beta-lactamases. The clinical choice of an oral expanded-spectrum cephalosporin will be based on patient acceptance, frequency of administration, and cost.

Administration, Oral↗
PubMed2005

Treating pregnancy-related nausea and vomiting with ginger.

OBJECTIVE: To review literature assessing the safety and efficacy of the use of ginger to treat nausea and vomiting in pregnancy. DATA SOURCES: Iowa Drug Information Service (1966-September 2004), International Pharmaceutical Abstracts (1971-September 2004), MEDLINE (1966-September 2004), and EMBASE (1966-September 2004) were searched. Key terms included ginger, nausea, vomiting, emesis, and pregnancy. DATA SYNTHESIS: Studies evaluating the safety and efficacy of ginger in the management of nausea and vomiting in pregnancy were reviewed. Various doses and forms of ginger were used to treat women during their first and second trimesters of pregnancy. Ginger has been shown to improve the symptoms of nausea and vomiting compared with placebo in pregnant women. CONCLUSIONS: While data are insufficient to recommend ginger universally and there are concerns with product quality due to limited regulation of dietary supplements, ginger appears to be a fairly low-risk and effective treatment for nausea and vomiting associated with pregnancy. In low doses, this may be appropriate for patients not responding to traditional first-line therapies.

Clinical Trials as Topic↗
PubMed2002

System approach to modeling metabolite formation from parent drug: a working example with methotrexate.

The aim of this methodological study was to present and exemplify a system-approach-based technology in modeling the formation of the metabolite from the parent drug. To represent this process, the parent-metabolite dynamic system was defined in such a way that the concentration-time profile of the parent drug was considered the input, while the concentration-time profile of the metabolite the output, of this system. The system-approach-based modeling technology was used to determine the model of the parent-metabolite dynamic system and to obtain the model-based estimates of the rate of metabolite formation, the rate of metabolic ratio and the mean time of metabolite formation. The technology was applied to concentration data for methotrexate and 7-hydroxymethotrexate in patients with psoriasis after a single oral methotrexate dose. Third-order linear models were selected as optimal to approximate the parent-metabolite dynamic systems representing the formation of 7-hydroxymethotrexate from methotrexate of these patients. The model-based estimates of the metabolic ratios ranged from 0.53 to 0.95. The model-based estimates of the mean times of formation of 7-hydroxymethotrexate from methotrexate ranged from 9.13 to 25.13 h. The model-based estimates of the rates of formation of 7-hydroxymethotrexate from methotrexate reached peak values (ranging from 0.03 to 0.11 h-1) in the time interval 1.5-4.5 h after administration of methotraxate. This study does not only introduce the method that may be useful in gaining insight into metabolite formation, but also presents a new example of the methodological, conceptual and computational uniformity of the system-approach-based technology in modeling various biomedical systems.

Administration, Oral↗