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Errors and linkage disequilibrium interact multiplicatively when computing sample sizes for genetic case-control association studies.

Single nucleotide polymorphisms (SNP) may be used in case-control designs to test for association between a SNP marker and a disease. Such designs may assume that the genotype data are reported without error. Our goal is quantifying the effects that errors have on sample size for case-control studies with haplotypes formed by a disease locus and a SNP marker locus in the presence of linkage disequilibrium (LD). We consider the effects of a recently published error model on 2x3 chi-square analysis. We study the joint relation of LD and errors with sample size for three specific genetic disease models and two settings each of marker allele frequencies (total of 6 studies). Minimal sample size necessary for fixed asymptotic power is estimated as a 4th degree polynomial in the variables S (error) and D' (LD measure) via a backward step-wise regression. We find that increased error rates lower power. In all studies, we observe that LD and errors interact in a non-linear fashion. In particular, regression analyses shows that several higher order interaction terms have coefficients significantly different from 0 in each study, with fraction of variance explained greater than 0.9999. Finally, the increase in sample size necessary to maintain constant asymptotic power and level of significance as a function of S is smallest when D' = 1 (perfect LD). The increase grows monotonically as D' decreases to 0.5 for all studies.

Case-Control Studies↗

[Estimation and optimization of the use of standard arterial input function for split-dose administration of N-isopropyl-p[123I]iodoamphetamine].

UNLABELLED: Use of a standard arterial input function and calibrating it by a single blood sample or a continuous arterial blood sample has been researched for a repeat CBF assessment with split-dose administration of N-isopropyl-p[123I]iodoamphetamine (IMP). METHODS: The study population consisted of 5 normal volunteers and 5 patients with cerebrovascular disease. IMP was injected twice (111 MBq/2 ml each) into the anti-cubital vein at a constant infusion speed for 1 min. The arterial input function was monitored during the study including a continuous measurement of radioactivity concentration of both the whole-blood and the octanol-soluble component (Real-Input Function, RIF). Standard input function was determined, and was calibrated either by a single blood sample or a continuous blood sample to estimate the Estimated-Input Function (EIF). Area-Under-the Curve (AUC) was then compared between RIF and EIF. RESULTS: In case EIF was estimated with a single blood sample, the minimum error of estimated AUC was obtained when calibrated at 7 minutes after either the 1st or 2nd injections. Deviation of AUC for [0, 30] was +/- 6.6%, and +/- 5.0%, respectively. If calibrated with a continuous blood sample, the minimum error of AUC with the continuous blood sampling period of 10 min for [0, 30] and [30, 60] was +/- 5.3% and +/- 4.0%, respectively. CONCLUSIONS: AUC of EIF with either a single or continuous blood sampling appeared to have reasonably small errors, suggesting the validity of the use of standardized input function in the split-dose IMP SPECT.

Adult↗

Sampling intercomparisons for aldehydes in simulated workplace air.

Thirty one laboratories of various EU Member States have participated in two interlaboratory comparisons in order to assess errors of personal sampling methods associated with both the sampling and the analytical steps. In contrast to conventional quality control schemes, this project particularly focuses attention on the sampling and identification step; it is executed by means of sampling exercises and has included discussions on potential sources of error. In a sampling exercise, participants come to a central facility and perform measurements on synthetic workplace air in a laboratory installation. Concentration levels of formaldehyde, acrolein, glutaraldehyde and acetaldehyde between 0.1 and 2 times the limit value for workplace air were prepared at various humidity levels and with acetone, occasionally, as interferent. Sampling times varied from 1-4 h. The related analytical work is performed at the analyst's own laboratory. The intention is for each participant to determine the observed value of the delivered standard atmosphere using the sampling method of his own choice. Trueness (bias), precision and relative overall uncertainty of each method-laboratory combination is calculated and verified towards compliance with EN 482, which outlines minimum performance criteria. The first challenge involved the precise gas phase generation of the selected analytes in high air flows (up to 300 1 min-1) and calculating the true value only by direct reference to primary standards. This was accomplished by modifying the capillary dosage injection technique so that reactive compounds, like low molecular mass aldehydes, could be dosed with the same accuracy and precision as unreactive solvents. A permeation tube with high emission rate was developed for formaldehyde. Up to ten different sampling techniques were evaluated. The measurement methods used by the majority of the participants were based on pumped sampling on silica cartridges (or tubes) and glass fiber filters, coated with 2,4-dinitrophenylhydrazine. It was observed that for formaldehyde, and in some cases for acetaldehyde and glutaraldehyde, the majority of the method-laboratory combinations complied with an overall uncertainty of 30%. The results for acrolein, however, indicated a systematic negative bias, often larger than minus 50% of the true value, caused by the decomposition of the acrolein DNPH derivative in the presence of excess acid and excess DNPH.

Air Pollutants, Occupational↗

Medication error in the care of HIV/AIDS patients: electronic surveillance, confirmation, and adverse events.

BACKGROUND: Medication error occurring during the care of HIV-infected patients may lead to treatment failure, drug toxicity, or even death. OBJECTIVE: The objective of this study was to ascertain and confirm 5 categories of medication error in the care of HIV-infected patients. RESEARCH DESIGN: This study was a retrospective study to describe the occurrence of preventable medication error and to determine if adverse events were associated with confirmed errors. A roster of medications for each category of potential errors was created. Computerized pharmacy records were scanned for all dispensing of these medications. Potential errors were confirmed by medical records abstraction. For the incorrect dosing, coadministration of contraindicated medications, and antiretroviral monotherapy error categories, random samples were chart reviewed for confirmation. For the remaining 2 error categories, all potential errors were chart reviewed. The positive predictive value (PPV) of potential errors, the incidence of confirmed error among all new prescription orders filled and the patient characteristics predicting likelihood of error confirmation were estimated for each error category. SUBJECTS: The study sample involved 5473 HIV-infected patients of the Kaiser Permanente Northern California (KPNC) health plan. RESULTS: Among the 5 error categories, PPVs ranged from a high of 80% for coadministration of contraindicated medications to <1% for antiretroviral monotherapy. Incidence of confirmed errors was 9.80 errors per 1000 new prescriptions dispensed for incorrect dosing, 9.51 errors per 1000 for contraindicated medications, and <1.00 for all other categories. Adverse events associated with confirmed errors were observed only in the contraindicated medications error category. The likelihood of a contraindicated medications error was significantly increased among patients >or=50 years of age and decreased among black patients. CONCLUSIONS: Use of electronic pharmacy records to ascertain true medication errors appears most reliable when conducting surveillance for contraindicated medications errors and less reliable for other error categories. Lack of confirmation is likely the result of patients' lack of adherence to drug regimens or providers' intentional deviation from accepted prescribing guidelines. Only confirmed contraindicated medications errors appear to be linked to adverse events.

AIDS-Related Opportunistic Infections↗

Strong feature sets from small samples.

For small samples, classifier design algorithms typically suffer from overfitting. Given a set of features, a classifier must be designed and its error estimated. For small samples, an error estimator may be unbiased but, owing to a large variance, often give very optimistic estimates. This paper proposes mitigating the small-sample problem by designing classifiers from a probability distribution resulting from spreading the mass of the sample points to make classification more difficult, while maintaining sample geometry. The algorithm is parameterized by the variance of the spreading distribution. By increasing the spread, the algorithm finds gene sets whose classification accuracy remains strong relative to greater spreading of the sample. The error gives a measure of the strength of the feature set as a function of the spread. The algorithm yields feature sets that can distinguish the two classes, not only for the sample data, but for distributions spread beyond the sample data. For linear classifiers, the topic of the present paper, the classifiers are derived analytically from the model, thereby providing an enormous savings in computation time. The algorithm is applied to cancer classification via cDNA microarrays. In particular, the genes BRCA1 and BRCA2 are associated with a hereditary disposition to breast cancer, and the algorithm is used to find gene sets whose expressions can be used to classify BRCA1 and BRCA2 tumors.

Breast Neoplasms↗

Downregulation of metastasis suppressor genes in malignant pheochromocytoma.

There is no reliable method currently available to predict malignant potential of pheochromocytoma based on conventional histology or genetic, molecular or immunohistochemical markers. Metastasis suppressor genes affect the spread of several cancers and, therefore, may provide promise as prognostic markers or therapeutic targets for malignant pheochromocytoma. We hypothesized that the downregulation of metastasis suppressor genes in malignant pheochromocytoma may play a role in malignant behavior. We applied quantitative real-time polymerase chain reaction (QRT-PCR) to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancer-related cellular events, such as cell growth regulation and apoptosis (nm23-H1, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRMS-1), invasion (CRMP-1) and cell adhesion (E-Cad and KiSS1). The study included 15 benign and 10 malignant pheochromocytomas. Six metastasis suppressor genes (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3 and E-Cad) were downregulated significantly in malignant compared to benign pheochromocytoma (p < 0.05, Mann-Whitney U-test). We applied a non-linear rule using median malignant value (MMV) as a threshold to use metastasis suppressor genes to distinguish malignant from benign samples. After cross-validation, the non-linear rule produced no errors in 10 malignant samples and 3 errors in the 15 benign samples, with an overall error rate of 12%. These results suggest that downregulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. Thus, we conclude that altered function of these metastasis suppressor gene pathways may play an important role in the malignant behavior of pheochromocytoma.

Adrenal Gland Neoplasms↗

The systematic component of phylogenetic error as a function of taxonomic sampling under parsimony.

The effect of taxonomic sampling on phylogenetic accuracy under parsimony is examined by simulating nucleotide sequence evolution. Random error is minimized by using very large numbers of simulated characters. This allows estimation of the consistency behavior of parsimony, even for trees with up to 100 taxa. Data were simulated on 8 distinct 100-taxon model trees and analyzed as stratified subsets containing either 25 or 50 taxa, in addition to the full 100-taxon data set. Overall accuracy decreased in a majority of cases when taxa were added. However, the magnitude of change in the cases in which accuracy increased was larger than the magnitude of change in the cases in which accuracy decreased, so, on average, overall accuracy increased as more taxa were included. A stratified sampling scheme was used to assess accuracy for an initial subsample of 25 taxa. The 25-taxon analyses were compared to 50- and 100-taxon analyses that were pruned to include only the original 25 taxa. On average, accuracy for the 25 taxa was improved by taxon addition, but there was considerable variation in the degree of improvement among the model trees and across different rates of substitution.

Classification↗

On the recording of sample times and parameter estimation from repeated measures pharmacokinetic data.

A pharmacokinetic screen has been advocated for the characterization of the population pharmacokinetics of drugs during Phase 3 clinical trials. A common perception encountered in the collection of such data is that the accuracy of sampling times relative to dose is inadequate. A prospective simulation study was carried out to evaluate the effect of error in the recording of sampling times on the accuracy and precision of population parameter estimates from repeated measures pharmacokinetic data. A two-compartment model with intravenous bolus input(s) (single and multiple doses) was assumed. Random and systematic error in sampling times ranging from 5-50% using profile (block) randomized design were introduced. Sampling times were simulated in EXCEL while concentration data simulation and analysis were done in NONMEM. The effect of error in sampling times was studied at levels of variability ranging from 15-45% for a drug assumed to be dosed at its elimination half-life. One hundred replicate data sets of 100 subjects each were simulated for each case. Although estimates of clearance (CL) and variability in clearance were robust for most of the sampling time errors, there was an increase in bias and imprecision in overall parameter estimation as intersubject variability was increased. If there is interest in parameters other than CL, then the design of prospective population studies should include procedures for minimizing the error in the recording of sample times relative to dosing history.

Computer Simulation↗

Assessing spatial fluctuations, temporal variability, and measurement error in estimated levels of disinfection by-products in tap water: implications for exposure assessment.

AIMS: To assess spatial fluctuations, temporal variability, and errors due to sampling and analysis in levels of disinfection by-products in routine monitoring tap water samples and in water samples collected in households within the same distribution system for an exposure assessment study. METHODS: Mixed effects models were applied to quantify seasonal effects and the degree to which trihalomethane (THM) levels vary among households or locations relative to variation over time within seasons for any given location. In a separate analysis, the proportion of total variation due to measurement error arising from sampling and analysis was also quantified. RESULTS: THM levels were higher in the summer relative to other seasons. Differences in the relative magnitude of the intra- and inter-household components of variation were observed between the two sets of THM measurements, with a greater proportion of the variation due to differences within seasons for the routine monitoring data and a greater proportion of the variation due to differences across locations for the exposure assessment study data. Such differences likely arose due to differences in the strategies used to select sites for sampling and in the time periods over which the data were collected. With the exception of bromodichloromethane, measurement errors due to sampling and analysis contributed a small proportion of the total variation in THM levels. CONCLUSIONS: The utility of routine monitoring data in assigning exposure in epidemiological studies is limited because such data may not represent the magnitude of spatial variability in levels of disinfection by-products across the distribution system. Measurement error contributes a relatively small proportion to the total variation in THM levels, which suggests that gathering a greater number of samples over time with fewer replicates collected at each sampling location is more efficient and would likely yield improved estimates of household exposure.

Chlorine↗

Evaluation of an in-house centrifugal hematology analyzer for use in veterinary practice.

OBJECTIVE: To compare CBC results obtained by use of an in-house centrifugal analyzer with results of a reference method. DESIGN: Prospective study. SAMPLE POPULATION: Blood samples from 147 dogs, 42 cats, and 60 horses admitted to a veterinary teaching hospital and from 24 cows in a commercial dairy herd. PROCEDURE: Results obtained with the centrifugal analyzer were compared with results obtained with an electrical-impedance light-scatter hematology analyzer and manual differential cell counting (reference method). RESULTS: The centrifugal analyzer yielded error messages for 50 of 273 (18%) samples. Error messages were most common for samples with values outside established reference ranges. Correlation coefficients ranged from 0.80 to 0.99 for Hct, 0.55 to 0.90 for platelet count, 0.76 to 0.95 for total WBC count, and 0.63 (cattle) to 0.82 (cats) to 0.95 (dogs and horses) for granulocyte count. Coefficients for mononuclear cell (combined lymphocyte and monocyte) counts were 0.56, 0.65, 0.68, and 0.92 for cats, horses, dogs, and cattle, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that there was an excellent correlation between results of the centrifugal analyzer and results of the reference method only for Hct in feline, canine, and equine samples; WBC count in canine and equine samples; granulocyte count in canine and equine samples; and reticulocyte count in canine samples. However, an inability to identify abnormal cells, the high percentage of error messages, particularly for samples with abnormal WBC counts, and the wide confidence intervals precluded reliance on differential cell counts obtained with the centrifugal analyzer.

Animals↗

A data compression algorithm for the electroencephalogram.

This paper describes a data compression algorithm for the EEG using a local error measure. The algorithm discards input signal samples provided they can be reconstructed from the stored samples with an error smaller than a given threshold, and according to simple reconstruction functions (the hold, the ramp, and the cosine). An equivalent (in terms of storage) sampling rate of 44 Hz is achieved without noticeable degradation of the signal quality for visual analysis. The method can be easily implemented for real time multichannel data compression/reconstruction.

Algorithms↗

Calculation of stable isotope enrichment tracer kinetic procedures.

The choice of method of expressing isotopic enrichment in tracer kinetic experiments utilizing stable isotopes was found to affect the calculation of tracee pool size and half-life. The most commonly used definition, the difference between enriched and natural abundance, i.e. atom percent excess, was found to result in significant error in model systems when the dose of tracer was 10% of the pool size. Errors in determining first-order rate constants of efflux and in pool sizes decreased with decreasing ratio of tracer to tracee. Error in determining pool size increased with longer 'sampling' periods, while error in determining the rate constant increased with shorter sampling periods. Of three less frequently used expressions of isotopic enrichment two were found to yield the exact answers in model systems. The correct expressions of isotopic enrichment were linear functions of the quantity of tracer in the system. A practical example demonstrated the effect of choice of expression of enrichment on estimates of whole body copper pool size and turnover in dairy cattle.

Animals↗

Clinical evaluation of an eccentric infrared photorefractor: the PowerRefractor.

PURPOSE: To evaluate the viability of the PowerRefractor as a screening tool for examining refractive errors in large samples of children. METHODS: The variability of the PowerRefractor was estimated using four patients. The refractive error was determined using cyclopentolate and tropicamide as cycloplegic agents and compared to that determined in a non-cycloplegic situation. In a second study, the data provided by the PowerRefractor were compared to results obtained by autorefractor or retinoscopy for 150 children aged from 6 months to 5 years. RESULTS: Variability study. Statistical analysis showed a statistically significant difference between cycloplegic and non-cycloplegic refraction for spherical and cylindrical refractive errors (p<0.0001 in all cases). There was no significant difference between the measurements made using tropicamide and cyclopentolate (p=0.33 and p=0.18, respectively). Comparison study. In 142 of 150 patients the difference between data obtained by the PowerRefractor and an autorefractor was within 1 D (spherical equivalent). However, there was a considerable difference between the data generated by the two methods in the remaining eight patients (up to 16 D). CONCLUSIONS: The PowerRefractor proved to be a reliable tool for estimating refractive errors in young children. The apparatus is easy to handle and the simultaneous examination of both eyes makes the PowerRefractor ideal for obtaining data on refractive errors in large samples.

Adolescent↗

Bias and random errors in historical data of exposure to organic solvents.

The biases and random errors in data from industrial hygiene measurements have been evaluated. Such data are often used for exposure assessment in epidemiologic studies by people who are not professional industrial hygienists. The quality of such data is, therefore, of paramount importance. Data sets from two investigations of the exposure to organic solvents in the same industry have been analyzed. The study shows that the errors and analysis of field samples are larger than errors determined from laboratory data but smaller than errors from other sources. One exception, in which laboratory errors are large, is when data originate from different ways of determining recovery. Very large biases may arise for certain combinations of analytes and extraction liquid when the "equilibrium method" is used. The data sets from the two investigations had a bias, which was as large as a factor of 5 to 10. This bias is believed to be caused by use of two different sampling strategies. In all industrial hygiene data, large random errors are embedded because of day-to-day variations in exposure levels; therefore, the data are mostly used grouped into three classes of low, medium, and high exposure. To do so is meaningful, as a large amount of data will compensate for misclassifications. But a large amount of data cannot compensate for the bias introduced when merging data generated under different sampling strategies. Data describing the same object, but originating from different sampling strategies, should not be pooled without proper tests, which show that data are comparable.(ABSTRACT TRUNCATED AT 250 WORDS)

Bias↗

[Patellar complications in total arthroplasty of the knee: a meta-analytic study].

Patellar complications during total knee arthroplasty (TKA) with and without prosthesis has been reported with great variability in the rates of patellar complications and has been noted by different authors. We decided to perform a meta-analysis study to find possible differences among them by measuring the effects of magnitude (EM), the rate risks (RR), and the number of patients (NP) who require this treatment. We found that in studies that include small samples, the aleatory errors are greater than those with larger samples, so the first would not be considered to estimate the effect of magnitude against control groups (without patellar prosthesis). When we carried out correct comparisons between these groups, the percentage of complications in the patellar group were reduced. We also see that the differences in patellar complications reported by different authors with a similar large number of samples are due to different levels of expertise in the surgical procedure employed. We conclude that a meta-analysis study will be necessary in Orthopedics.

Arthroplasty, Replacement, Knee↗

Precision of Cavalieri sections and slices with local errors.

Cavalieri sections--and more recently Cavalieri slices, especially in combination with non-invasive scanning--are widely used to estimate volumes. Physical Cavalieri slices are also increasingly used to estimate neuron numbers via the optical fractionator. In either case, the prediction of the error variance is important to assess optimal sample sizes. The error variance consists of two components, one due to the variation among the true contents of sections or slices, and the other due to local or 'nugget' errors. The latter may arise for instance estimating section areas by point counting discrete particles in slices or disectors. In this paper, a fairly comprehensive set of prediction formulae is presented to separate both variance components.

Female↗

Scientific vs. statistical inference: the problem of multiple contrasts in clinical research.

The problem of type 1 error rates in clinical medicine research is discussed and a new measure of evaluating the incidences of type 1 error is presented. Three measures, including the experimentwise error rate, the error rate per experiment, and the percentage error rate are used to compute the type 1 error in a sample of clinical research. The results suggest the presence of a substantial incidence of type 1 error in the sampled research. The implications for statistical and scientific inferences are briefly discussed and some possible solutions explored.

Research↗

Quantitative analysis of mannitol polymorphs. X-ray powder diffractometry--exploring preferred orientation effects.

Mannitol is a polymorphic parmaceutical excipient, which commonly exists in three forms: alpha, beta and delta. Each polymorph has a needle-like morphology, which can give preferred orientation effects when analysed by X-ray powder diffractometry (XRPD) thus providing difficulties for quantitative XRPD assessments. The occurrence of preferred orientation may be demonstrated by sample rotation and the consequent effects on X-ray data can be minimised by reducing the particle size. Using two particle size ranges (<125 and 125-500 microm), binary mixtures of beta and delta mannitol were prepared and the delta component was quantified. Samples were assayed in either a static or rotating sampling accessory. Rotation and reducing the particle size range to <125 microm halved the limits of detection and quantitation to 1 and 3.6%, respectively. Numerous potential sources of assay errors were investigated; sample packing and mixing errors contributed the greatest source of variation. However, the rotation of samples for both particle size ranges reduced the majority of assay errors examined. This study shows that coupling sample rotation with a particle size reduction minimises preferred orientation effects on assay accuracy, allowing discrimination of two very similar polymorphs at around the 1% level.

Excipients↗