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Obtaining informed consent for genetic studies: The multiethnic study of atherosclerosis.

Studies of DNA may yield important information about atherosclerosis. To determine how often study participants' consent to examine DNA is denied and the factors associated with that denial, information was collected on participants in the US Multiethnic Study of Atherosclerosis (MESA) during 2000-2004. Permission was sought for preparation of DNA, transformation of cells into cell lines, evaluation of genes related to heart and other health conditions, and access to DNA by private companies. Of the 5,494 participants at entry, 897 (16.3%) refused consent for some items and 247 (4.5%) completely denied consent. At a second examination 18 months later, 819 (15.0%) partially refused and 229 (4.2%) completely denied consent. Age among men (odds ratio per 10 years = 0.68, 95% confidence interval: 0.54, 0.85; p = 0.004), ethnicity (odds ratio for African American = 2.34, 95% confidence interval: 1.66, 3.32; p < 0.001), and field center (p < 0.001) were associated with complete denial. For those giving partial consent, the most common item refused was access to DNA by private companies (baseline: 99%; second examination: 90%); younger age, male gender, and African-American ethnicity were associated with refusal. The authors concluded that a small percentage of participants in epidemiologic studies refuse consent for DNA studies, and the majority are concerned about sharing their DNA data with industry.

Age Factors↗

IMpRH server: an RH mapping server available on the Web.

SUMMARY: The INRA-Minnesota Porcine Radiation Hybrid (IMpRH) Server provides both a mapping tool (IMpRH mapping tool) and a database (IMpRH database) of officially submitted results. The mapping tool permits the mapping of a new marker relatively to markers previously mapped on the IMpRH panel. The IMpRH database is the official database for submission of new results and queries. The database not only permits the sharing of public data but also semi-private and private data.

Animals↗

Assessing delivery of the five 'As' for patient-centered counseling.

The '5As' model of behavior change provides a sequence of evidence-based clinician and office practice behaviors (Assess, Advise, Agree, Assist, Arrange) that can be applied in primary care settings to address a broad range of behaviors and health conditions. Although the 5As approach is becoming more widely adopted as a strategy for health behavior change counseling, practical and standardized assessments of 5As delivery are not widely available. This article provides clinicians and researchers with alternatives for assessment of 5As implementation for both quality improvement, and for research and evaluation purposes, and presents several practical tools they may wish to use. Sample instruments for tracking delivery of the 5As and related tools that are in the public domain are provided to facilitate integration of self-management support into clinical care. We discuss the strengths and limitations of the various assessment approaches. Promising and practical measures to assess the 5As exist for both quality improvement and research purposes. Additional validation is needed on almost all current procedures, and both clinicians and researchers are encouraged to use these instruments and share the resulting data.

Counseling↗

Multivariate analyses of the risk of insulin-dependent diabetes mellitus for siblings of insulin-dependent diabetic patients.

Multivariate models for the risk of insulin-dependent diabetes mellitus for siblings of patients with insulin-dependent diabetes were developed using logistic regression analysis. The individuals studied in this report are full siblings of the insulin-dependent diabetic patients diagnosed at Children's Hospital of Pittsburgh between 1964 and 1982. For all siblings considered together, the sharing of two (but not one) HLA haplotypes, the presence of insulin-dependent diabetes in a parent, and being relatively young at the time the proband in the family was diagnosed were significantly associated with increased risk. On the other hand, B7 + siblings had a significantly decreased risk compared to B7--siblings, indicating the presence of an HLA-linked protective gene for the development of the disease. There was a significant interaction between sharing two HLA haplotypes and maternal age at the time of birth; for non-HLA-identical siblings, risk increased with increased maternal age, but maternal age had little or no effect on the risk for HLA-identical siblings. When non-HLA-identical siblings (0 or 1 HLA haplotypes shared) were analyzed separately, only the presence of insulin-dependent diabetes in one of the parents and increased maternal age at the time of birth of the sibling were found to be significantly associated with increased risk. Both of the totally non-HLA-identical diabetic siblings (neither HLA haplotype shared) in this data set had a parent with insulin-dependent diabetes, indicating that at least one HLA haplotype must be inherited in common with an affected family member for diabetes to develop. For HLA-identical siblings, the significant variables were the age of the sibling when the proband was diagnosed, the possession of B7, and maternal age at the time of birth of the sibling, and all three were negatively associated with risk.

Adult↗

Report of the European Working Group on Dementia Drug Guidelines Meeting--Brussels, November 1997.

A conference was held in Brussels in November 1997 under the auspices of the International Working Group for Harmonization of Dementia Drug Guidelines. The meeting reviewed development of European Dementia Guidelines, with a focus on the roles of academics, industry, the European Commission, the European Parliament, and the European Medicines Evaluation Agency. The objectives of the meeting were to review progress in development of dementia drug guidelines across Europe, with particular reference to harmonization of these efforts with developments in other countries, particularly the United States and Japan. Specific topics covered included issues in developing trials to address disease progression, very mild disease, severe disease, and the non-Alzheimer dementias. Clinical trial designs and the types of measures chosen in these new areas are unlikely to be the same as those used in previous trials for symptomatic relief of mild-to-moderate Alzheimer disease. The assessment tools need to be specific for the purpose of the trial and ongoing research is still needed in this area. Little is known about the natural progression of disease based on the types of measures used in clinical trials. Evidence suggests that rates of decline are variable and nonlinear. Improved collaboration between academics, industry personnel, and regulators, particularly through the sharing of placebo data sets, could allow considerable advances in our understanding of natural disease progression.

Aged↗

Hepatitis C infection in patients undergoing liver retransplantation.

BACKGROUND: There is concern that repeat orthotopic liver transplantation in patients with hepatitis C virus (HCV) infection may be associated with poor long-term survival. The specific aims of the current analysis were to determine (1) the prevalence of HCV infection in a large cohort of patients undergoing retransplantation, (2) define the impact of HCV infection on patient survival, and (3) determine the predictors of outcome of HCV-positive patients undergoing retransplantation for graft failure not caused by primary nonfunction. METHODS: We analyzed the United Network of Organ Sharing (UNOS) registry data of 1539 adults undergoing orthotopic liver retransplantation between January 1990 and February 1996; 357 patients (23%) were HCV-positive. RESULTS: The prevalence of HCV infection increased significantly from 6.5% in 1990 to 38.4% in 1995 (P<0.0001). Comparing the HCV-positive versus HCV-negative groups, there were no significant differences with regards to age, time to retransplantation, biochemical parameters immediately preceding retransplantation, UNOS registry status mix, or cause of graft failure (% with primary nonfunction). However, Kaplan-Meier analysis demonstrated significantly diminished survival in the HCV-positive group (P=0.0038, log-rank test; relative risk, 1.36; 95% confidence interval: 1.07-1.71). Multivariate logistic regression analysis of the subgroup of HCV-positive patients undergoing retransplantation for graft failure not caused by primary nonfunction identified preoperative serum bilirubin and serum creatinine as significant predictors of outcome. Seven of 207 (3.4%) patients undergoing retransplantation died of recurrent HCV in their second allografts. CONCLUSION: The prevalence of HCV infection in patients undergoing retransplantation appears to have significantly increased since 1990. HCV infection is an independent risk factor for death after retransplantation. However, acceptable results are attainable in highly selected patients, i.e., those patients without severe hyperbilirubinemia and renal failure, and retransplantation remains the only viable option for patients whose allografts fail because of recurrent disease.

Adolescent↗

HIV-positive renal recipients can achieve survival rates similar to those of HIV-negative patients.

BACKGROUND: Although patients positive for HIV were once thought to be unsuitable candidates for kidney transplantation, their increasing numbers with end-stage renal disease (ESRD) and the introduction of highly active antiretroviral therapy has indicated that they should no longer be excluded for transplantation. To counteract suggestions that human immunodeficiency virus (HIV) patients received suboptimal kidneys, we provide studies of kidneys transplanted from the same donor into patients with and without HIV. METHODS: United Network for Organ Sharing kidney transplant data between 1997 and 2004 were analyzed. Graft and patient survival of 38 HIV patients who had received a renal transplant were compared with the survival of 38 recipients who had received a graft from the same donor. RESULTS: The 38 HIV-positive recipients were younger (49.0 vs. 52.3 years, P=0.14) and had lower peak panel-reactive antibodies (PRA; 5.1% vs. 15.6%, P=0.07) when compared with their bilateral donor to HIV-negative recipients. Sirolimus was used more frequently in HIV patients than in non-HIV patients (36.8% vs. 23.7%, P=0.09). The serum creatinine at 1, 3, and 5 years posttransplantation were higher in HIV patients when compared to non-HIV patients. Although not statistically significant, graft survival was higher among HIV-positive patients compared with their negative controls (76.1% vs. 65.1% at 5 years, P=0.21), as was patient survival (91.3% vs. 87.3% at 5 years, P=0.72). More grafts failed due to death with a functioning graft than rejection in HIV-positive patients. CONCLUSION: This study supports the position that there is no longer an ethical question surrounding the use of kidneys for HIV-positive patients.

Female↗

Conditional quantum phase gate between two 3-state atoms.

We propose a scheme for conditional quantum logic between two 3-state atoms that share a quantum data bus such as a single mode optical field in cavity QED systems, or a collective vibrational state of trapped ions. Making use of quantum interference, our scheme achieves successful conditional phase evolution without any real transitions of atomic internal states or populating the quantum data bus. In addition, it requires only common addressing of the two atoms by external laser fields.

Journal Article↗

Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal.

OBJECTIVE: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the context of autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN2) syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC), which are caused by activating germline mutations in the RET proto-oncogene. The aim of this study was to characterize the RET mutational spectrum in MEN2 families and apparently sporadic MTC (AS-MTC) cases originating from the central region of Portugal. SUBJECTS AND METHODS: We studied a total of 82 individuals (64 affected and 18 family members), comprising five MEN2 families (four MEN2A and one MEN2B), as well as 53 AS-MTC cases. RET germline mutations were screened using PCR-DNA sequencing, SSCP and RFLP. The haplotypes associated with recurrent mutations were determined by fragment analysis of microsatellite markers, and by RFLP, in the case of intragenic polymorphisms. RESULTS: Frequency of the Cys611Tyr (TGC-TAC) mutation was significantly increased in this region of Portugal, due to the fact that three apparently unrelated MEN2A/FMTC families, out of the five in which mutations were identified, harboured this specific mutation. Haplotype analysis revealed that a common haplotype was shared between two of these three families. We have also characterized a novel RET mutation, Arg886Trp, located in the tyrosine kinase domain, which was found in an AS-MTC case. CONCLUSIONS: There are regional specificities in the relative frequency of RET mutations, which are consistent with a cluster-like distribution of specific disease-causing mutations, as a result of the inheritance of a shared haplotype. These data, along with the finding of a novel RET mutation (Arg886Trp), have important implications towards facilitating and improving the molecular diagnosis of hereditary MTC on a regional basis.

Adult↗

Phaeochromocytoma, new genes and screening strategies.

Following recent advances in the genetics of phaeochromocytomas and paragangliomas, the members of the European Network for the Study of Adrenal Tumours (ENS@T) Phaeochromocytoma Working Group have decided to share their genotyping data and to propose European recommendations for phaeochromocytoma/functional paraganglioma (PH/FPGL) genetic testing. Germline DNA from 642 patients was analysed by ENS@T teams. In 166 patients (25.9%) the disease was familial and caused by germline mutations in VHL (56), SDHB (34), SDHD (31), RET (31) or NF1 (14), causing von Hippel-Lindau disease, SDHB- or SDHD-PH/FPGL syndromes, multiple endocrine neoplasia type 2 (MEN 2) and type 1 neurofibromatosis (NF1), respectively. In almost 60% of inherited cases it was possible to formulate a probable genetic diagnosis based on family history and/or typical syndromic presentation. Genetic testing revealed mutations in 12.7% of cases with an apparently sporadic presentation. Several clinical characteristics, such as young age at onset, the presence of bilateral, extra-adrenal or multiple tumours or a malignant tumour, should be seen as indications for genetic testing. The ENS@T Phaeochromocytoma Working Group recommends the genetic testing of all patients with PH and FPGL and suggests a practice algorithm for the management of their exploration.

Adrenal Gland Neoplasms↗

Internet as clinical information system: application development using the World Wide Web.

Clinical computing application development at Columbia-Presbyterian Medical Center has been limited by the lack of a flexible programming environment that supports multiple client user platforms. The World Wide Web offers a potential solution, with its multifunction servers, multiplatform clients, and use of standard protocols for displaying information. The authors are now using the Web, coupled with their own local clinical data server and vocabulary server, to carry out rapid prototype development of clinical information systems. They have developed one such prototype system that can be run on most popular computing platforms from anywhere on the Internet. The Web paradigm allows easy integration of clinical information with other local and Internet-based information sources. The Web also simplifies many aspects of application design; for example, it includes facilities for the use of encryption to meet the authors' security and confidentiality requirements. The prototype currently runs on only the Web server in the Department of Medical Informatics at Columbia University, but it could be run on other Web servers that access the authors' clinical data and vocabulary servers. It could also be adapted to access clinical information from other systems with similar server capabilities. This approach may be adaptable for use in developing institution-independent standards for data and application sharing.

Computer Communication Networks↗

Potential use of extensible markup language for radiology reporting: a tutorial.

One of the main goals of radiology is to communicate imaging information to aid in patient management. Information standards can facilitate communication and help realize this goal. Extensible Markup Language (XML) is a new information transmission standard that was developed to meet the growing need for robust, large-scale World Wide Web applications. XML notation provides a compact document representation scheme that allows radiology reports to be transmitted over the Web as universally understandable, self-defining documents. XML documents can include a report-specific document type definition (DTD) that defines the allowable data fields and values. XML may also be used to generate data entry forms for radiology reporting and help physicians improve the efficiency of the reporting process. XML documents can be used to store reporting results directly, thus allowing pertinent data to be shared on the Web. An XML-based approach can allow users to link information to entities outside the information systems of a given institution. XML-based methods and applications have the potential to promote development of robust radiology reporting systems and integration with broader, enterprise-wide information systems.

Databases as Topic↗

Spinal input to thalamic VL neurons: evidence for direct spinothalamic effects.

1. The postsynaptic actions of afferents ascending in the ventrolateral quadrant and dorsal columns of the spinal cord were studied in neurons in the ventrolateral nucleus of the thalamus (VL) (n = 138) by use of intracellular recording procedures. Neurons were identified by their monosynaptic input from the cerebellum and, when possible, their antidromic activation from the motor cortex. The possible occurrence of monosynaptic transmission along spinothalamic fibers was investigated by estimating the intrathalamic delay time of postsynaptic responses and by examining the occurrence of temporal facilitation to double-shock stimulation. The experiments were performed in cats anesthetized with alpha-chloralose. 2. The majority of neurons (86%) responded with excitatory or inhibitory postsynaptic potentials to stimulation of the ascending paths. The response latencies of excitation on stimulation of the ventral quadrants at C3 ranged from 2.9 to 18 ms. Evidence for monosynaptic excitation after stimulation of (spinothalamic) afferents ascending in the ventrolateral quadrants was obtained for a number of neurons (n = 30). For these neurons, estimated intrathalamic delays were less than 1 ms and/or the neurons did not display temporal facilitation to double shocks. All the shortest latency responses (from C3) showed evidence of monosynaptic transmission. It is estimated that approximately 19-39% of neurons sampled may receive monosynaptic input. The spinal conduction velocities of the direct projections ranged from 10 to 35 m/s (median 20 m/s). 3. Much of the ascending input was mediated polysynaptically. For afferents ascending in the ventrolateral quadrant, estimated intrathalamic delays were greater than 1.5 ms and/or the postsynaptic responses displayed temporal facilitation to double shocks. The shortest latency from C3 of a polysynaptic response was 5 ms. Spatial interactions were observed between polysynaptic inputs from the ventrolateral quadrants and the dorsal columns, indicating that at least some of the pathways to VL are shared. 4. The data show that many neurons in the VL receive input ascending from the spinal cord via direct and indirect routes. Somatosensory information reaching VL could serve to adjust, during the course of movement execution, the cerebellar commands relayed by VL to the motor cortex.

Animals↗

An interaction between the catechol O-methyltransferase and serotonin transporter promoter region polymorphisms contributes to tridimensional personality questionnaire persistence scores in normal subjects.

Persistence (RD2) is a subscale of the reward dependence trait, one of the three major personality factors assessed by the Tridimensional Personality Questionnaire (TPQ). Subjects with high RD2 scores are characterized as industrious, hard-working, ambitious, perfectionistic. TPQ scores were examined in 577 normal subjects inventoried for two common genetic polymorphisms, the catechol O-methyltransferase (COMT) valine to methionine (val to met) amino acid substitution that determines high and low enzyme activity, and the serotonin transporter promoter region 44 bp deletion (5-HTTLPR) linked in some studies to harm avoidance or neuroticism. When TPQ RD2 scores are grouped by COMT and 5-HTTLPR polymorphisms and analyzed by two-way ANOVA, significant main effects for COMT (F = 2. 98, p = 0.05) and 5-HTTLPR (F = 4.27, p = 0.04) and a significant interaction COMT x 5-HTTLPR (F = 6.18, p = 0.002) are observed. In the presence of COMT homozygosity (val/val or met/met genotypes), the presence of the short 5-HTTLPR allele raises RD2 scores. The effect of these two polymorphisms on RD2 was also examined using a within-families design. Siblings in our data set who shared identical genotypes had significantly correlated RD2 scores (intraclass coefficient = 0.34, F = 2.03, p = 0.002, n = 67), whereas sibs with dissimilar genotypes in at least one polymorphism showed no significant correlation for RD2 scores (intraclass coefficient = 0.105, F = 1.23, p = 0.16, n = 92).

Adolescent↗

Bio++: a set of C++ libraries for sequence analysis, phylogenetics, molecular evolution and population genetics.

BACKGROUND: A large number of bioinformatics applications in the fields of bio-sequence analysis, molecular evolution and population genetics typically share input/output methods, data storage requirements and data analysis algorithms. Such common features may be conveniently bundled into re-usable libraries, which enable the rapid development of new methods and robust applications. RESULTS: We present Bio++, a set of Object Oriented libraries written in C++. Available components include classes for data storage and handling (nucleotide/amino-acid/codon sequences, trees, distance matrices, population genetics datasets), various input/output formats, basic sequence manipulation (concatenation, transcription, translation, etc.), phylogenetic analysis (maximum parsimony, markov models, distance methods, likelihood computation and maximization), population genetics/genomics (diversity statistics, neutrality tests, various multi-locus analyses) and various algorithms for numerical calculus. CONCLUSION: Implementation of methods aims at being both efficient and user-friendly. A special concern was given to the library design to enable easy extension and new methods development. We defined a general hierarchy of classes that allow the developer to implement its own algorithms while remaining compatible with the rest of the libraries. Bio++ source code is distributed free of charge under the CeCILL general public licence from its website http://kimura.univ-montp2.fr/BioPP.

Algorithms↗

Individual freedom versus collective responsibility: an ethicist's perspective.

Philosophical theories of collective action have produced a number of alternative accounts of the rationality and morality of self-interest and altruism. These have obvious applications to communicable disease control, the avoidance of antibiotic resistance, the responsibility of healthcare professionals to patients with serious communicable diseases, and the sharing of personal data in epidemiological research.

Editorial↗

Regulation of germline stem cell proliferation downstream of nutrient sensing.

Stem cells have recently attracted significant attention largely due to their potential therapeutic properties, but also because of their role in tumorigenesis and their resemblance, in many aspects, to cancerous cells. Understanding how stem cells are regulated, namely with respect to the control of their proliferation and differentiation within a functional organism, is thus primordial to safely profit from their therapeutic benefits. Here, we review recent advances in the understanding of germline stem cell proliferation control by factors that respond to the nutritional status and/or insulin signaling, through studies performed in C. elegans and Drosophila. Together, these data uncover some shared fundamental features that underlie the central control of cellular proliferation within a target stem cell population in an organism. These features may indeed be conserved in higher organisms and may apply to various other stem cell populations.

Journal Article↗

Breaking barriers through collaboration: the example of the Cell Migration Consortium.

Understanding complex integrated biological processes, such as cell migration, requires interdisciplinary approaches. The Cell Migration Consortium, funded by a Large-Scale Collaborative Project Award from the National Institute of General Medical Science, develops and disseminates new technologies, data, reagents, and shared information to a wide audience. The development and operation of this Consortium may provide useful insights for those who plan similarly large-scale, interdisciplinary approaches.

Cell Movement↗