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Generating benchmarks for multiple sequence alignments and phylogenetic reconstructions.
We present a new probabilistic model of evolution of RNA-, DNA-, or protein-like sequences and a tool rose that implements this model. By insertion, deletion and substitution of characters, a family of sequences is created from a common ancestor. During this artificial evolutionary process, the "true" history is logged and the "correct" multiple sequence alignment is created simultaneously. We also allow for varying rates of mutation within the sequences making it possible to establish so-called sequence motifs. The results are suitable for the evaluation of methods in multiple sequence alignment computation and the prediction of phylogenetic relationships.
Profitability of a university-based clinic using benchmark time lengths for clinical encounters.
Reductions in reimbursement are applied to all physicians in a region equally. However, physicians do not practice in equivalent situations. For example, there are few fiscal allowances for academic functions associated with teaching and administration. Furthermore, university-based physicians may practice in clinical venues that cannot be as efficient as nonuniversity sites. Unavoidable inefficiencies may include (1) the costs of maintaining one historical record for a large noncontiguous practice; (2) university-required holiday schedules and sick leave, making university personnel less productive; (3) noncompetitive overhead rates assigned to clinic components by university financial offices; (4) university-based accounting systems that are not designed for effective cost control and the timely generation of useful management information; and (5) poorly managed billing services. Until now, declining reimbursements have generally led to sufficient efficiencies in delivery so that revenues and expenses can be in equilibrium.
Study finds inadequate mental health coverage in benchmark plans for new child health program.
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A CHF program that focuses on best practices and benchmarks.
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Ecotoxicological evaluation of perfluorooctanesulfonate (PFOS).
Based on available toxicity data, protective screening-level concentrations of PFOS were calculated for aquatic and terrestrial organisms. Using the Great Lakes Initiative, water concentrations of PFOS were calculated to protect aquatic plants and animals. The screening plant value (SPV) protective of aquatic algae and macrophytes was calculated as 2.3 mg PFOS/L. The secondary chronic value protective of aquatic organisms was 1.2 microg PFOS/L. The screening-value water concentrations less than or equal to 1.2 microg PFOS/L would not pose a potential risk to aquatic organisms. Because the aquatic benchmark is based on the most sensitive species, this benchmark should also be protective of other aquatic organisms, including amphibians. The tissue-based TRV for fish was determined to be 87 mg PFOS/kg ww. For terrestrial plants, a screening benchmark was determined to be 1.3 mg PFOS/kg soil ww or 1.5 mg PFOS/kg soil dw, whereas for soil invertebrates such as earthworms the benchmark value was 39 mg PFOS/kg dw soil or 33 mg PFOS/kgww soil. For avian species, dietary, ADI, and egg yolk-based benchmarks were determined as 0.28mg PFOS/kg diet, 0.021mg PFOS/kg bw/d, and 1.7 microg PFOS/mL yolk, respectively. Benchmarks for serum and liver for the protection of avian species were 1.0 microg PFOS/mL and 0.6 microg PFOS/gww, respectively. However, no-effect levels in laboratory studies suggest actual population-level effects would not be expected to occur until a concentration of 6.0mg PFOS/kg in the diet, 5.0 microg PFOS/gww in the liver, or 9.0 microg PFOS/mL in the serum was exceeded, thus indicating the conservative nature of the benchmarks.
Nitroaromatic munition compounds: environmental effects and screening values.
Available data on the occurrence, transport, transformation, and toxicity of eight nitroaromatic munition compounds and their degradation products, TNT, TNB, DNB, DNA, 2-ADNT, RDX, HMX, and tetryl were used to identify potential fate in the environment and to calculate screening benchmarks or safe environmental levels for aquatic and terrestrial organisms. Results of monitoring studies revealed that some of these compounds persist at sites where they were produced or processed. Most of the compounds are present in soil, sediment, and surface water or groundwater at military sites. Soil adsorption coefficients indicate that these chemicals are only moderately adsorbed to soil and may leach to groundwater. Most of these compounds are transformed by abiotic or biotic mechanisms in environmental media. Primary transformation mechanisms involve photolysis (TNT, RDX, HMX, tetryl), hydrolysis (tetryl), and microbial degradation (TNT, TNB, DNB, DNA, 2-ADNT, and HMX). Microbial degradation for both nitro and nitramine aromatic compounds involves rapid reduction of nitro groups to amino groups, but further metabolism is slow. With the exception of DNB, complete mineralization did not usually occur under the conditions of the studies. RDX was resistant to microbial degradation. Available ecotoxicological data on acute and chronic studies with freshwater fish and invertebrates were summarized, and water quality criteria or ecotoxicological screening benchmarks were developed. Depending on the available data, criteria/benchmarks were calculated according to USEPA Tier I or Tier II guidelines. The munitions chemicals are moderately to highly toxic to freshwater organisms, with chronic screening values < 1 mg/L. For some chemicals, these low values are caused by inherent toxicity; in other cases, they result from the conservative methods used in the absence of data. For nonionic organic munitions chemicals, sediment quality benchmarks were calculated (based on Kow values and the final chronic value) according to USEPA guidelines. Available data indicate that none of the compounds is expected to bioconcentrate. In the same manner in which reference doses for humans are based on studies with laboratory animals, reference doses or screening benchmarks for wildlife may also be calculated by extrapolation among mammalian species. Chronic NOAELs for the compounds of interest were determined from available laboratory studies. Endpoints selected for wildlife species were those that diminish population growth or survival. Equivalent NOAELs for wildlife were calculated by scaling the test data on the basis of differences in body weight. Data on food and water intake for seven selected wildlife species--short-tailed shrew, white-footed mouse, meadow vole, cottontail rabbit, mink, red fox, and whitetail deer--were used to calculate NOAELs for oral intake. In the case of TNB, a comparison of toxicity data from studies conducted with both the white-footed mouse and the laboratory rat indicates that the white-footed mouse may be more resistant to the toxic effects of chemicals than the laboratory rat and may further indicate the lesser sensitivity of wildlife species to chemical insult. Chronic NOAEL values for the test species based on the laboratory studies indicate that, by the oral route of exposure, TNB and RDX are not highly toxic to mammalian species. However, as seen with TNB, values are less conservative when chronic studies are available or when studies were conducted with wildlife species. Insufficient data were located to calculate NOAELs for avian species. In the absence of criteria or guidelines for terrestrial plants, invertebrates, and soil heterotrophic processes, LOECs were used as screening benchmarks for effect levels in the environment. In most cases, too few data were available to derive a screening benchmark or to have a high degree of confidence in the benchmarks that were derived. (ABSTRACT TRUNCATED)
How well do HapMap haplotypes identify common haplotypes of genes? A comparison with haplotypes of 334 genes resequenced in the environmental genome project.
One of the goals of the International HapMap Project is the identification of common haplotypes in genes. However, HapMap uses an incomplete catalogue of single nucleotide polymorphisms (SNPs) and might miss some common haplotypes. We examined this issue using data from the Environmental Genome Project (EGP) which resequenced 335 genes in 90 people, and thus, has a nearly complete catalogue of gene SNPs. The EGP identified a total of 45,243 SNPs, of which 10,780 were common SNPs (minor allele frequency >or=0.1). Using EGP common SNP genotype data, we identified 1,459 haplotypes with frequency >or=0.05 and we use these as "benchmark" haplotypes. HapMap release 16 had genotype information for 1,573 of 10,780 (15%) EGP common SNPs. Using these SNPs, we identified common HapMap haplotypes (frequency >or=0.05) in each of the four HapMap ethnic groups. To compare common HapMap haplotypes to EGP benchmark haplotypes, we collapsed benchmark haplotypes to the set of 1,573 SNPs. Ninety-eight percent of the collapsed benchmark haplotypes could be found as common HapMap haplotypes in one or more of the four HapMap ethnic groups. However, collapsing benchmark haplotypes to the set of SNPs available in HapMap resulted in a loss of haplotype information: 545 of 1,459 (37%) benchmark haplotypes were uniquely identified, and only 25% of genes had all their benchmark haplotypes uniquely identified. We resampled the EGP data to examine the effect of increasing the number of HapMap SNPs to 5 million, and estimate that approximately 40% of common SNPs in genes will be sampled and that half of the genes will have sufficient SNPs to identify all common haplotypes. This inability to distinguish common haplotypes of genes may result in loss of power when examining haplotype-disease association.
Public health implications of 1990 air toxics concentrations across the United States.
Occupational and toxicological studies have demonstrated adverse health effects from exposure to toxic air contaminants. Data on outdoor levels of toxic air contaminants have not been available for most communities in the United States, making it difficult to assess the potential for adverse human health effects from general population exposures. Emissions data from stationary and mobile sources are used in an atmospheric dispersion model to estimate outdoor concentrations of 148 toxic air contaminants for each of the 60,803 census tracts in the contiguous United States for 1990. Outdoor concentrations of air toxics were compared to previously defined benchmark concentrations for cancer and noncancer health effects. Benchmark concentrations are based on standard toxicological references and represent air toxic levels above which health risks may occur. The number of benchmark concentrations exceeded by modeled concentrations ranged from 8 to 32 per census tract, with a mean of 14. Estimated concentrations of benzene, formaldehyde, and 1,3-butadiene were greater than cancer benchmark concentrations in over 90% of the census tracts. Approximately 10% of all census tracts had estimated concentrations of one or more carcinogenic HAPs greater than a 1-in-10,000 risk level. Twenty-two pollutants with chronic toxicity benchmark concentrations had modeled concentrations in excess of these benchmarks, and approximately 200 census tracts had a modeled concentration 100 times the benchmark for at least one of these pollutants. This comprehensive assessment of air toxics concentrations across the United States indicates hazardous air pollutants may pose a potential public health problem.
Determining clinically important differences in health status measures: a general approach with illustration to the Health Utilities Index Mark II.
The objective of this article was to describe and illustrate a comprehensive approach for estimating clinically important differences (CIDs) in health-related quality-of-life (HR-QOL). A literature review and pilot study were conducted to determine whether effect size-based benchmarks are consistent with CIDs obtained from other approaches. CIDs may be estimated based primarily upon effect sizes, supplemented by more traditional anchor-based methods of benchmarking (i.e. direct, cross-sectional or longitudinal approaches). A literature review of articles discussing CIDs provided comparative data on effect sizes for various chronic conditions. A pilot study was then conducted to estimate the minimum CID of the Health Utilities Index (HUI) Mark II, and to compare the observed between-group differences observed in a recent randomised trial of an acute stroke intervention with this benchmark. The use of standardised effect size benchmarks has a number of advantages-for example, effect sizes are efficient, widely accepted outside HR-QOL, and have well accepted benchmarks based upon external anchors. In addition, our literature review and pilot study suggest that effect size-based CID benchmarks are similar to those which would be obtained using more traditional methods. For most HR-QOL instruments, we do not know the changes in score which constitute CIDs of various magnitudes. This makes interpretation of HR-QOL results from clinical trials difficult, and having a benchmarking process which is relatively straightforward would be highly desirable.
Comparison of Affymetrix GeneChip expression measures.
MOTIVATION: In the Affymetrix GeneChip system, preprocessing occurs before one obtains expression level measurements. Because the number of competing preprocessing methods was large and growing we developed a benchmark to help users identify the best method for their application. A webtool was made available for developers to benchmark their procedures. At the time of writing over 50 methods had been submitted. RESULTS: We benchmarked 31 probe set algorithms using a U95A dataset of spike in controls. Using this dataset, we found that background correction, one of the main steps in preprocessing, has the largest effect on performance. In particular, background correction appears to improve accuracy but, in general, worsen precision. The benchmark results put this balance in perspective. Furthermore, we have improved some of the original benchmark metrics to provide more detailed information regarding precision and accuracy. A handful of methods stand out as providing the best balance using spike-in data with the older U95A array, although different experiments on more current arrays may benchmark differently. AVAILABILITY: The affycomp package, now version 1.5.2, continues to be available as part of the Bioconductor project (http://www.bioconductor.org). The webtool continues to be available at http://affycomp.biostat.jhsph.edu CONTACT: rafa@jhu.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Automated methods of predicting the function of biological sequences using GO and BLAST.
BACKGROUND: With the exponential increase in genomic sequence data there is a need to develop automated approaches to deducing the biological functions of novel sequences with high accuracy. Our aim is to demonstrate how accuracy benchmarking can be used in a decision-making process evaluating competing designs of biological function predictors. We utilise the Gene Ontology, GO, a directed acyclic graph of functional terms, to annotate sequences with functional information describing their biological context. Initially we examine the effect on accuracy scores of increasing the allowed distance between predicted and a test set of curator assigned terms. Next we evaluate several annotator methods using accuracy benchmarking. Given an unannotated sequence we use the Basic Local Alignment Search Tool, BLAST, to find similar sequences that have already been assigned GO terms by curators. A number of methods were developed that utilise terms associated with the best five matching sequences. These methods were compared against a benchmark method of simply using terms associated with the best BLAST-matched sequence (best BLAST approach). RESULTS: The precision and recall of estimates increases rapidly as the amount of distance permitted between a predicted term and a correct term assignment increases. Accuracy benchmarking allows a comparison of annotation methods. A covering graph approach performs poorly, except where the term assignment rate is high. A term distance concordance approach has a similar accuracy to the best BLAST approach, demonstrating lower precision but higher recall. However, a discriminant function method has higher precision and recall than the best BLAST approach and other methods shown here. CONCLUSION: Allowing term predictions to be counted correct if closely related to a correct term decreases the reliability of the accuracy score. As such we recommend using accuracy measures that require exact matching of predicted terms with curator assigned terms. Furthermore, we conclude that competing designs of BLAST-based GO term annotators can be effectively compared using an accuracy benchmarking approach. The most accurate annotation method was developed using data mining techniques. As such we recommend that designers of term annotators utilise accuracy benchmarking and data mining to ensure newly developed annotators are of high quality.
Verbal estimation of peak exertion intensity.
The objectives of this research were to investigate the accuracy and precision with which trained and untrained participants estimate the magnitude of forceful exertion and to evaluate the mathematical relationship between actual and estimated exertion. Three groups of participants estimated, as a percentage of maximum voluntary contraction (%MVC), the magnitude of submaximal exertion for 12 simulated tasks. In addition to the control group, one group was exposed to one physical benchmark (100% MVC) and another to three benchmarks (25%, 75%, and 100% MVC) prior to force estimation. Error (estimated minus actual) significantly decreased (p < .0001) from 14% MVC to 4% MVC with one benchmark and to -3% MVC with three benchmarks, as compared with the control group. Furthermore, the standard deviation decreased significantly (p < .0001 ) from the control group (16.6% MVC) to the one-benchmark group (13.8% MVC) to the three-benchmark group (11.6% MVC), indicating improved precision. Significant interaction effects were observed, but their impact on main effects was negligible. Also, linear, power, and logarithmic regression models described the relationship between perceived and actual exertion equally well (R2 = .64-.81). Applications of this research include improving the accuracy and precision of field-based psychophysical estimates of forceful exertion for epidemiological research and other field-based analyses.
Educating the pediatrician of the 21st century: defining and implementing a competency-based system.
PURPOSE: The final product of the Accreditation Council for Graduate Medical Education (ACGME) Outcomes Project is to improve health care through ensuring the competence of physicians during their training and beyond. Its success depends on a paradigm shift to a competency-based model of medical education. This article presents an overview of the model and describes the first stages of this multistep transition in a university setting. Our hope is to raise awareness of the impact on the pediatric community at large and provide a foundation on which other educators can continue to build. METHODS: The ACGME established 6 domains of competence as the first step in the paradigm shift. To begin work on the second step of establishing benchmarks for evaluation of competence and thresholds at which they should be achieved, the educational leadership from the primary care departments formed a work group with the support of a Health Resources and Services Administration grant. RESULTS: Review of the literature led us to embark on a stepwise process for initiating a competency-based system of medical education. We established the benchmarks by a process of individual effort followed by group consensus. These benchmarks, in the aggregate, permit an evaluator to determine whether a given competency has been achieved. The next phases of step 2 required setting thresholds for the demonstration of competence and finally establishing consensus regarding the threshold for competence at each level of training for each specific benchmark. To accomplish the latter, we surveyed the program directors of the 202 accredited pediatric training programs that are members of the Association of Pediatric Program Directors. Eighty-one members (40%) completed our survey. Although some controversy existed for thresholds during the postgraduate-year-1 level, majority consensus was reached for nearly all benchmarks at the upper levels of training. Impact of the shift to competencies for medical students and practicing physicians is also reviewed. CONCLUSION: Having defined the benchmarks and thresholds for the 6 ACGME domains of competence, we are well positioned to move to step 3: developing the necessary tools to evaluate competence. The move to competency-based education impacts the entire pediatric community. Lessons learned from our experience may be generalized and thus be of value to the community at large.
Impact of the Minimum Pricing Policy and introduction of brand (generic) substitution into the Pharmaceutical Benefits Scheme in Australia.
PURPOSE: To describe the effects of introducing the Minimum Pricing Policy (MPP) and generic (brand) substitution in 1990 and 1994 respectively on the dispensing of Pharmaceutical Benefits Scheme (PBS) prescriptions both at the aggregate and individual patient level. METHODS: The relative proportion of prescriptions with a brand premium and those at benchmark was examined 4 years after introduction of the MPP and again 5 years later after generic substitution by pharmacists was permitted. To determine the impact of a price signal at the individual level, case studies involving a patient tracking methodology were conducted on two drugs (fluoxetine and ranitidine) that received a brand premium. RESULTS: From a zero base when the MPP was introduced in 1990, there were 5.4 million prescriptions (17%) dispensed for benchmark products 4 years later in 1994. At this stage generic (brand) substitution by pharmacists was then permitted and the market share of benchmark brands increased to 45% (25.2 million) by 1999. In the patient tracking studies, a significantly lower proportion of patients was still taking the premium brand of fluoxetine 3 months after the introduction of a price signal compared with patients taking paroxetine which did not have a generic competitor. This was also the case for the premium brand of ranitidine when compared to famotidine. The size of the price signal also had a marked effect on dispensing behaviour with the drug with the larger premium (fluoxetine) showing a significantly greater switch away from the premium brand to the benchmark product. CONCLUSIONS: The introduction in 1990 of the Minimum Pricing Policy without allowing generic substitution had a relatively small impact on the selection of medicines within the Pharmaceutical Benefits Scheme. However the effect of generic substitution at the pharmacist level, which was introduced in December 1994, resulted in a marked increase in the percentage of eligible PBS items dispensed at benchmark. Case studies showed a larger premium resulted in a greater shift of patients from drugs with a brand premium to the benchmark alternative.
Physicians' response to length-of-stay profiling.
One of the techniques adopted recently by certain hospitals to meet the competitive pressure for reducing costs is physician profiling. Profiling produces periodic reports that compare a physician's resource consumption to a benchmark figure. This study analyzes the effectiveness and implications of one hospital's introduction of physician patient length-of-stay profiling. Data for 24,000 patients treated by 400 physicians in 450 diagnosis-related groups over 42 months were analyzed, including both preprofiling and postprofiling periods. Statistical tests examined whether more physicians achieved the length-of-stay benchmark after profiling was introduced, controlling for physician, disease category (diagnosis-related group), and patient severity level. First, the results establish a significant increase in the percentage of physicians who achieve the length-of-stay benchmark after the introduction of profiling. Second, it was found that physicians who had initially failed to meet the benchmark reduced their patients' average length of stay much more than those physicians who initially achieved the benchmark. Further, reductions occurred primarily at intermediate severity levels, and in diagnosis-related groups with a large economic impact for the hospital. Although the profiling program did achieve the objective of reducing patient length of stay, further improvement may be possible. First, providing different benchmarks or targets for different physicians may extend the improvement to a greater percentage of all physicians involved. Second, an analysis of monthly data on total weighted procedures reveals that the reduction in length of stay resulted in an increase in the number of procedures performed per patient day. This finding suggests that to achieve a reduction in hospital costs and charges, profiling programs should be combined with process improvement initiatives.
Application of health information to hazardous air pollutants modeled in EPA's Cumulative Exposure Project.
Relatively little is known about the spectrum of health effects, and the scope and level of ambient air concentrations of those pollutants regulated under the Clean Air Act as "hazardous air pollutants". The U.S. Environmental Protection Agency's (USEPA) Cumulative Exposure Project uses currently available emissions inventories, from a variety of source types, and an atmospheric dispersion model to provide estimates of ambient concentrations for 148 hazardous air pollutants (HAPs) in over 60,000 census tracts for the year 1990. This paper uses currently available hazard information for those pollutants and provides a database of potential regulatory threshold concentrations of concern, or "benchmark concentrations," and a methodology for prioritizing and characterizing the quality of the data. In order to demonstrate application of the database and prioritization scheme to outputs from the Cumulative Exposure Project, comparisons were made with the maximum modeled concentration of each individual hazardous air pollutant across the census tracts. Of the 197 benchmark concentrations for cancer and non-cancer (long- and short-term exposures) effects compiled for the study, approximately one half were exceeded with a predominance of exceedance of cancer benchmarks. While the number of benchmark concentrations available to fully characterize potential health effects of these pollutants was limited (approximately 80 percent of HAPs identified as cancer concerns had benchmark concentrations for cancer and 50 percent of all HAPs had non-cancer benchmark concentrations) and there was greater uncertainty in derivation of maximum modeled air concentrations than other levels, the comparison between the two was a useful approach for providing an indication of public health concern from hazardous air pollutants.