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A new approach to integrating data from multiple informants in psychiatric assessment and research: mixing and matching contexts and perspectives.

OBJECTIVE: When there exists no single source of information (informant) to validly measure a characteristic, it is typically recommended that data from multiple informants be used. In psychiatric assessment and research, however, multiple informants often provide discordant data, which further confuse the measurement. Strategies such as arbitrarily choosing one informant or using the data from all informants separately generate further problems. This report proposes a theory to explain observed patterns of interinformant discordance and suggests a new approach to using data from multiple informants to measure characteristics of interest. METHOD: Using the example of assessment of developmental psychopathology in children, the authors propose a model in which the choice of informants is based on conceptualizing the contexts and perspectives that influence expression of the characteristic of interest and then identifying informants who represent those contexts and perspectives in such a way as to have the weaknesses of one informant canceled by the strengths of another. RESULTS: Applications of this approach to several datasets indicate that when these principles are followed, a more reliable and valid consensus measure is obtained, and failure to obtain a reliable, valid measure is indicative of some deviation from the principles. CONCLUSIONS: In obtaining a consensus measure, the issue is not determining how many informants are needed but choosing the right set of informants.

Adult↗

Metabolomics: an emerging post-genomic tool for nutrition.

The post-genomic era has been driven by the development of technologies that allow the function of cells and whole organisms to be explored at the molecular level. Metabolomics is concerned with the measurement of global sets of low-molecular-weight metabolites. Metabolite profiles of body fluids or tissues can be regarded as important indicators of physiological or pathological states. Such profiles may provide a more comprehensive view of cellular control mechanisms in man and animals, and raise the possibility of identifying surrogate markers of disease. Metabolomic approaches use analytical techniques such as NMR spectroscopy and MS to measure populations of low-molecular-weight metabolites in biological samples. Advanced statistical and bioinformatic tools are then employed to maximise the recovery of information and interpret the large datasets that are generated. Metabolomics has already been used to study toxicological mechanisms and disease processes and offers enormous potential as a means of investigating the complex relationship between nutrition and metabolism. Examples include the metabolism of dietary substrates, drug-induced disturbances of lipid metabolites in type 2 diabetes mellitus and the therapeutic effects of vitamin supplementation in the treatment of chronic metabolic disorders.

Biomarkers↗

Mining gene expression data for positive and negative co-regulated gene clusters.

MOTIVATION: Analysis of gene expression data can provide insights into the positive and negative co-regulation of genes. However, existing methods such as association rule mining are computationally expensive and the quality and quantities of the rules are sensitive to the support and confidence values. In this paper, we introduce the concept of positive and negative co-regulated gene cluster (PNCGC) that more accurately reflects the co-regulation of genes, and propose an efficient algorithm to extract PNCGCs. RESULTS: We experimented with the Yeast dataset and compared our resulting PNCGCs with the association rules generated by the Apriori mining algorithm. Our results show that our PNCGCs identify some missing co-regulations of association rules, and our algorithm greatly reduces the large number of rules involving uncorrelated genes generated by the Apriori scheme. AVAILABILITY: The software is available upon request.

Algorithms↗

On the use of a hospital information system in evaluating clinical care: a case report.

In this paper we describe, as an example, how we obtained the information needed to evaluate a newly introduced protocol for ordering X-rays for ankle trauma patients. Extensive use was made of available data and facilities of the hospital information system (HIS). Procedures for collecting the required additional data, which were not recorded in the HIS but were needed to evaluate the protocol, were embedded in the current medical and administrative routine of the emergency room. These additional data were also stored in the HIS. Periodically all data were downloaded to a personal computer to analyse the impact of using the protocol on quality of care and costs. In total 1241 patients entered the study, and for 1149 patients a complete dataset was obtained. The sensitivity and specificity of the protocol at the threshold value which was used during the initial study period was 0.77 and 0.80. The reduction in the number of ankle X-rays due to the protocol was significant when compared with a strategy of ordering an X-ray for every ankle trauma patient visiting the emergency room.

Ankle Injuries↗

Long-term personality data collection in support of spaceflight and analogue research.

This is a review of past and present research into personality and performance at the University of Texas (UT) Human Factors Research Project. Specifically, personality trait data collected from astronauts, pilots, Antarctic personnel, and other groups over a 15-yr period is discussed with particular emphasis on research in space and space analogue environments. The UT Human Factors Research Project conducts studies in personality and group dynamics in aviation, space, and medicine. Current studies include personality determinants of professional cultures, team effectiveness in both medicine and aviation, and personality predictors of long-term astronaut performance. The Project also studies the design and effectiveness of behavioral strategies used to minimize error and maximize team performance in safety-critical work settings. A multi-year personality and performance dataset presents many opportunities for research, including long-term and follow-up studies of human performance, analyses of trends in recruiting and attrition, and the ability to adapt research design to operational changes and methodological advances. Special problems posed by such long-duration projects include issues of confidentiality and security, as well as practical limitations imposed by current peer-review and short-term funding practices. Practical considerations for ongoing dataset management include consistency of assessment instruments over time, variations in data acquisition from one year to the next, and dealing with changes in theory and practice that occur over the life of the project. A fundamental change in how research into human performance is funded would be required to ensure the ongoing development of such long-duration research databases.

Adaptation, Psychological↗

Evaluation of different weight correction methods for antenatal serum screening using data from two multi-centre programmes.

Weight correction of serum markers is widely used when screening for Down's syndrome and open neural tube defects (NTD) because marker concentrations decrease with increasing maternal weight. Log-linear regression is frequently used for determining weight correction factors, but recently reciprocal-linear regression has been suggested to have advantages. We compared both methods of weight correction using data from two screening programmes carried out by this laboratory, one using alpha-fetoprotein (AFP) and total human chorionic gonadotrophin (HCG) (n = 129,143) and the other, AFP and free beta-HCG (n = 39,982). The reciprocal-linear method fitted the data more closely but did not significantly alter the detection rate or screen positive rate (SPR) for Down's syndrome or NTD with either dataset. Without correction, women heavier or lighter than average weight had significantly different SPRs for Down's syndrome and NTD compared with those weighing close to the median weight. Both correction methods smoothed out the variability in the SPR for Down's syndrome to a similar degree, but reciprocal-linear regression was much better at reducing the variability in SPR for NTD and its use is therefore worthwhile.

Biomarkers↗

The effect of oligonucleotide microarray data pre-processing on the analysis of patient-cohort studies.

BACKGROUND: Intensity values measured by Affymetrix microarrays have to be both normalized, to be able to compare different microarrays by removing non-biological variation, and summarized, generating the final probe set expression values. Various pre-processing techniques, such as dChip, GCRMA, RMA and MAS have been developed for this purpose. This study assesses the effect of applying different pre-processing methods on the results of analyses of large Affymetrix datasets. By focusing on practical applications of microarray-based research, this study provides insight into the relevance of pre-processing procedures to biology-oriented researchers. RESULTS: Using two publicly available datasets, i.e., gene-expression data of 285 patients with Acute Myeloid Leukemia (AML, Affymetrix HG-U133A GeneChip) and 42 samples of tumor tissue of the embryonal central nervous system (CNS, Affymetrix HuGeneFL GeneChip), we tested the effect of the four pre-processing strategies mentioned above, on (1) expression level measurements, (2) detection of differential expression, (3) cluster analysis and (4) classification of samples. In most cases, the effect of pre-processing is relatively small compared to other choices made in an analysis for the AML dataset, but has a more profound effect on the outcome of the CNS dataset. Analyses on individual probe sets, such as testing for differential expression, are affected most; supervised, multivariate analyses such as classification are far less sensitive to pre-processing. CONCLUSION: Using two experimental datasets, we show that the choice of pre-processing method is of relatively minor influence on the final analysis outcome of large microarray studies whereas it can have important effects on the results of a smaller study. The data source (platform, tissue homogeneity, RNA quality) is potentially of bigger importance than the choice of pre-processing method.

Algorithms↗

Random walk models for bayesian clustering of gene expression profiles.

The analysis of gene expression temporal profiles is a topic of increasing interest in functional genomics. Model-based clustering methods are particularly interesting because they are able to capture the dynamic nature of these data and to identify the optimal number of clusters. We have defined a new Bayesian method that allows us to cope with some important issues that remain unsolved in the currently available approaches: the presence of time dislocations in gene expression, the non-stationarity of the processes generating the data, and the presence of data collected on an irregular temporal grid. Our method, which is based on random walk models, requires only mild a priori assumptions about the nature of the processes generating the data and explicitly models inter-gene variability within each cluster. It has first been validated on simulated datasets and then employed for the analysis of a dataset relative to serum-stimulated fibroblasts. In all cases, the results have been promising, showing that the method can be helpful in functional genomics research.

Journal Article↗

Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions.

MOTIVATION: Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene-gene interaction or epistasis) and environmental factors (gene-environment interaction). Detecting and characterizing interactions among multiple factors is both a statistical and a computational challenge. To address this problem, we have developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe the MDR approach and an MDR software package. RESULTS: We developed a program that integrates MDR with a cross-validation strategy for estimating the classification and prediction error of multifactor models. The software can be used to analyze interactions among 2-15 genetic and/or environmental factors. The dataset may contain up to 500 total variables and a maximum of 4000 study subjects. AVAILABILITY: Information on obtaining the executable code, example data, example analysis, and documentation is available upon request. SUPPLEMENTARY INFORMATION: All supplementary information can be found at http://phg.mc.vanderbilt.edu/Software/MDR.

Algorithms↗

Machine learning and word sense disambiguation in the biomedical domain: design and evaluation issues.

BACKGROUND: Word sense disambiguation (WSD) is critical in the biomedical domain for improving the precision of natural language processing (NLP), text mining, and information retrieval systems because ambiguous words negatively impact accurate access to literature containing biomolecular entities, such as genes, proteins, cells, diseases, and other important entities. Automated techniques have been developed that address the WSD problem for a number of text processing situations, but the problem is still a challenging one. Supervised WSD machine learning (ML) methods have been applied in the biomedical domain and have shown promising results, but the results typically incorporate a number of confounding factors, and it is problematic to truly understand the effectiveness and generalizability of the methods because these factors interact with each other and affect the final results. Thus, there is a need to explicitly address the factors and to systematically quantify their effects on performance. RESULTS: Experiments were designed to measure the effect of "sample size" (i.e. size of the datasets), "sense distribution" (i.e. the distribution of the different meanings of the ambiguous word) and "degree of difficulty" (i.e. the measure of the distances between the meanings of the senses of an ambiguous word) on the performance of WSD classifiers. Support Vector Machine (SVM) classifiers were applied to an automatically generated data set containing four ambiguous biomedical abbreviations: BPD, BSA, PCA, and RSV, which were chosen because of varying degrees of differences in their respective senses. Results showed that: 1) increasing the sample size generally reduced the error rate, but this was limited mainly to well-separated senses (i.e. cases where the distances between the senses were large); in difficult cases an unusually large increase in sample size was needed to increase performance slightly, which was impractical, 2) the sense distribution did not have an effect on performance when the senses were separable, 3) when there was a majority sense of over 90%, the WSD classifier was not better than use of the simple majority sense, 4) error rates were proportional to the similarity of senses, and 5) there was no statistical difference between results when using a 5-fold or 10-fold cross-validation method. Other issues that impact performance are also enumerated. CONCLUSION: Several different independent aspects affect performance when using ML techniques for WSD. We found that combining them into one single result obscures understanding of the underlying methods. Although we studied only four abbreviations, we utilized a well-established statistical method that guarantees the results are likely to be generalizable for abbreviations with similar characteristics. The results of our experiments show that in order to understand the performance of these ML methods it is critical that papers report on the baseline performance, the distribution and sample size of the senses in the datasets, and the standard deviation or confidence intervals. In addition, papers should also characterize the difficulty of the WSD task, the WSD situations addressed and not addressed, as well as the ML methods and features used. This should lead to an improved understanding of the generalizablility and the limitations of the methodology.

Algorithms↗

The implementation of guidelines and computerised forms improves the completeness of cancer pathology reporting. The CROPS project: a randomised controlled trial in pathology.

The aim of this study was to determine whether reporting guidelines and computerised form-based reports improve the completeness of histopathological cancer data available for patient management and population cancer registration and to evaluate the acceptability of the intervention. The study was a randomised controlled trial with a split unit design and stratified cluster randomisation. All 16 hospital pathology laboratories in Wales were randomly allocated to report either breast or colorectal resection specimens by computerised form or conventional free text. 1044 reports were analysed in the study arm, 998 in the control arm. Use of pre-defined forms led to a 28.4% (95% confidence interval (CI): 15.7-41.2%) increase in complete reporting of a minimum dataset required for cancer registration and a 24.5% (95% CI: 11.0-38.0%) increase in complete reporting of minimum data required for patient management. Form-based reporting was acceptable to pathologists and preferred by clinicians. In conclusion, guidelines and computerised forms significantly improve the quality of histopathology reporting.

Breast Neoplasms↗

Optimum numerical integration methods for estimation of area-under-the-curve (AUC) and area-under-the-moment-curve (AUMC).

Eleven numerical methods for estimation of AUC (including 4 new methods) and 22 methods for AUMC (including 8 new methods) were tested on large simulated noisy datasets representing bolus, oral and infusion concentration-time profiles. Some methods were unacceptable because their mean error was large; these included a commonly recommended form of the linear trapezoidal rule for AUMC. Others, notably Lagrange and cubic spline methods, were unacceptable because the variance of their estimates was large. These methods should be abandoned. A simple and easily programmed new method, parabolas-through-the-origin then log-trapezoidal rule, performed especially well.

Numerical Analysis, Computer-Assisted↗

Development and validation of a patient-specific predictive instrument for the need for dose reduction in chemotherapy for breast cancer: a potential decision aid for the use of myeloid growth factors.

A predictive instrument for chemotherapy dose reductions would help optimize delivery of planned chemotherapy and rationalize the use of myeloid growth factors. We analyzed data on 833 women with breast cancer treated with cyclophosphamide, doxorubicin, and fluorouracil, for six cycles in two phase III clinical trials. From the first study ( n=323), we generated a logistic regression model that predicts an individual patient's probability of receiving significantly reduced chemotherapy, defined as less than 85% of the planned dose over cycles 2-6, using data generated from cycle 1. The model was validated on data from the second study ( n=510). The predictive model's variables include nadir absolute neutrophil count (ANC) in cycle 1 (OR: 0.14, 95% CI: 0.06-0.30, P<0.001) and percent drop of platelets between day 1 and the nadir in cycle 1 (OR: 1.04, 95% CI: 1.02-1.05, P<0.001). Both variables are dose adjusted based on the chemotherapy cycle 1 dose. The model's discriminatory performance was good (ROC area=0.82), as was the calibration of predicted with actual frequencies of dose reductions. In the validation dataset, model variables remained significant, with an ROC area of 0.78 and good calibration. In summary, we devised and validated a predictive instrument that uses data from a patient's first cycle of chemotherapy to compute the probability of requiring a significant chemotherapy dose reduction on subsequent cycles. This instrument could help clinicians select patients who will benefit from early administration of myeloid growth factors.

Adult↗

Intracluster correlation coefficients in cluster randomized trials: empirical insights into how should they be reported.

BACKGROUND: Increasingly, researchers are recognizing that there are many situations where the use of a cluster randomized trial may be more appropriate than an individually randomized trial. Similarly, the need for appropriate standards of reporting of cluster trials is more widely acknowledged. METHODS: In this paper, we describe the results of a survey to inform the appropriate reporting of the intracluster correlation coefficient (ICC)--the statistical measure of the clustering effect associated with a cluster randomized trial. RESULTS: We identified three dimensions that should be considered when reporting an ICC--a description of the dataset (including characteristics of the outcome and the intervention), information on how the ICC was calculated, and information on the precision of the ICC. CONCLUSIONS: This paper demonstrates the development of a framework for the reporting of ICCs. If adopted into routine practice, it has the potential to facilitate the interpretation of the cluster trial being reported and should help the development of new trials in the area.

Cluster Analysis↗

Measles: how many hospitalised cases are we missing?

We aimed to determine whether the Victorian measles surveillance system had missed hospitalised cases of measles during an inter-epidemic period. We searched the Victorian Inpatient Minimum Dataset (VIMD) for the period 1 January 1997 to 30 June 1998 to identify patients with ICD-9 discharge codes for measles (055). The data were compared with that held in the Victorian measles surveillance dataset. The hospital case notes of patients identified in the VIMD but not in the measles surveillance dataset were reviewed systematically to determine whether the patients met case definitions for laboratory-confirmed or clinically compatible measles. Sixteen admissions (15 patients) were identified with a measles ICD-9 code. Eight patients were not identified in the measles surveillance dataset. Of these, one was a laboratory confirmed case of measles and two met a clinical case definition but all should have been notified to the Department of Human Services as suspected cases. While the small number of missed notifications is encouraging in terms of overall measles surveillance, it highlights important deficiencies in the awareness of hospital staff of their role in the control of measles, particularly as Australia moves towards the elimination of measles.

Adult↗

A generic minimization random allocation and blinding system on web.

BACKGROUND: Minimization is a dynamic randomization method for clinical trials. Although recommended by many researchers, the utilization of minimization has been seldom reported in randomized trials mainly because of the controversy surrounding the validity of conventional analyses and its complexity in implementation. However, both the statistical and clinical validity of minimization were demonstrated in recent studies. Minimization random allocation system integrated with blinding function that could facilitate the implementation of this method in general clinical trials has not been reported. SYSTEM OVERVIEW: The system is a web-based random allocation system using Pocock and Simon minimization method. It also supports multiple treatment arms within a trial, multiple simultaneous trials, and blinding without further programming. METHODS: This system was constructed with generic database schema design method, Pocock and Simon minimization method and blinding method. It was coded with Microsoft Visual Basic and Active Server Pages (ASP) programming languages. And all dataset were managed with a Microsoft SQL Server database. Some critical programming codes were also provided. SIMULATIONS AND RESULTS: Two clinical trials were simulated simultaneously to test the system's applicability. Not only balanced groups but also blinded allocation results were achieved in both trials. DISCUSSIONS AND CONCLUSIONS: Practical considerations for minimization method, the benefits, general applicability and drawbacks of the technique implemented in this system are discussed. Promising features of the proposed system are also summarized.

Clinical Trials as Topic↗

Predictors of relapse rate in MS clinical trials.

BACKGROUND: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. METHODS: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, sex, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (relapsing remitting [RR] and secondary progressive [SP]). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. RESULTS: The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p < 0.05). A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses, and more enhancing lesions in T1 at entry. The fitted Poisson model shows that disease duration (estimate = -0.02) and previous relapse number (estimate = 0.59 for one, 0.91 for two, and 1.45 for three or more relapses vs no relapses) remain. The authors were able to confirm these findings in a second, independent dataset. CONCLUSIONS: The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate. Disease course did not contribute independently because its effect is covered by the pre-study relapse rate. Gadolinium enhancement status, given the other covariates, has no significant influence on the on-study relapse rate.

Age Factors↗

Clustering methods applied to allele sharing data.

Here we focus on using clustering methods to disentangle the interacting factors that lead to the presentation of complex diseases. Relative pairs are placed in discrete subgroups, or classes, based upon their pattern of allele sharing at a sequence of markers and on concomitant risk factors. The relationship between the locus information and the affectation status of the relative pairs within each subgroup then can be assessed. Cluster analysis (CLA) and latent class analysis (LCA) were applied to sibling allele sharing data from GAW11 simulated data, and to an existing Alzheimer's disease (AD) dataset. Both methods were able to identify markers linked to all 3 disease loci in the GAW11 data. LCA and CLA also replicated regions of chromosomes identified in an analysis of the AD data using affected-sib-pair methods. These analyses indicate that classification tools may be useful for detecting susceptibility genes for complex traits.

Aged↗