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Recent progress in the diagnosis and therapy for veno-occlusive disease of the liver.

Veno-occlusive disease (VOD) is one of the severe complications of the liver, which may occur after hematopoietic stem cell transplantation (HSCT). Although an early diagnosis is important to initiate antithrombotic therapy before serious organ failure, the widely used clinical criteria only become clinically fulfilled at an advanced stage of disease. Liver biopsy provides useful findings for the diagnosis of VOD, however, in the later or less severe stages of VOD liver biopsy may provide false-negative sampling error because the biopsy sample may be too small to evaluate the whole liver. In addition it may be difficult to follow the clinical course with repeat biopsy in individual cases. Imaging diagnosis of VOD including gray-scale US, Doppler US, and MRI have been reported as convenient and useful. Color-Doppler US is superior because of its specificity and sensitivity. Blood sampling tests including factor VII, protein C, N-terminal propeptide for type III procollagen (P-III-P) and hyarulonic acid have predictive value, and their measurement may simply be another way to evaluate early hepatic impairment. Since no optimal treatment for VOD has been established as yet, the prophylaxis of VOD or early initiation of treatment is important. These new diagnostic approaches for VOD may provide a direction to resolve the clinical problems of VOD such as the time of initiation of therapy, the therapeutic regimen of choice, and the cessation of therapy.

Anticoagulants↗

Rapid immunotyping of B-cell non-Hodgkin's lymphomas by flow cytometry. A comparison with the standard frozen-section method.

The authors compared immunotyping (IT) results obtained by both standard frozen section (FS) and flow cytometry (FC) methods on 218 biopsies suggestive of lymphoma to learn the advantages of each method. The independent interpretations of the FS and FC IT results were concordant in 93% (202 of 218) of cases. The 16 cases with discordance were reviewed and seven causes for discrepancy found: methodologic problems, focal lymphomatous involvement, more sensitive light chain detection by FC, inadequate sample for FC, interpretation error, sample mislabeling for FC, and unexplained. Eleven of the concordant B-cell non-Hodgkin's lymphomas (NHLs) studied by FC did not have a kappa:lambda ratio of 3 or greater or 0.5 or less and were shown to express light chain restriction by a D-value of 15 or greater with the use of statistical analysis of the kappa and lambda histograms or by multiparameter analysis of large versus small cells. The authors found both methods to be effective for phenotyping lymphomas, however, each has distinct features, making them complementary in their applications.

Antibodies, Monoclonal↗

Fine needle aspiration biopsy of primary bone tumors.

A review of 66 consecutive fine needle aspiration biopsies of primary bone tumors revealed that 48 (73%) were diagnostic. Twelve (18%) yielded inadequate specimens unsatisfactory for diagnosis, and five (8%) yielded specimens adequate for partial diagnosis. The only error, presumably attributable to sampling error, was an unappreciated dedifferentiated osteosarcoma arising in an otherwise typical giant cell tumor. Fine needle aspiration biopsy obviated the need for open biopsy in 24 patients and simplified surgery in an additional 24 patients by establishing the diagnosis before surgical intervention. A solitary soft tissue recurrence of a giant cell tumor has been the only local recurrence. A review of 26 consecutive patients with osteosarcoma revealed that seven tumors were diagnosed by primary open biopsy. Nineteen patients had fine needle aspiration biopsy, of which 15 were diagnostic and four required supplemental open biopsy. The elapsed time between the initial office visit and the diagnostic confirmation averaged 5 days for patients requiring open biopsy compared with 0 days for patients whose fine needle aspiration biopsy was diagnostic. The total estimated charge for fine needle aspiration biopsy of a distal femoral osteosarcoma was $1060.00 compared with $4312.25 for open biopsy. There have been no local recurrences in patients in either group. Fine needle aspiration biopsy provides an accurate, safe, efficient, well tolerated, and cost-effective method for diagnosing classic primary bone tumors, including osteosarcoma.

Biopsy, Needle↗

Direct phase determination by entropy maximization and likelihood ranking: status report and perspectives.

A new multisolution phasing method based on entropy maximization and likelihood ranking, proposed for the specific purpose of extending probabilistic direct methods to the field of macromolecules, has been implemented in two different computer programs and applied to a wide variety of problems. The latter comprise the determination of small crystal structures from X-ray diffraction data obtained from single crystals or from powders, and from electron diffraction data partially phased by image processing of electron micrographs, the ab initio generation and ranking of phase sets for small proteins; and the improvement of poor quality phases for a larger protein at medium resolution under constraint of solvent flatness. These applications show that the primary goal of this new method - namely increasing the accuracy and sensitivity of probabilistic phase indications compared with conventional direct methods - has been achieved. The main components of the method are (1) a tree-directed search through a space of trial phase sets; (2) the saddle-point method for calculating joint probabilities of structure factors, using entropy maximization; (3) likelihood-based scores to rank trial phase sets and prune the search tree; (4) efficient schemes, based on error-correcting codes, for sampling trial phase sets; (5) a statistical analysis of the scores for automatically selecting reliable phase indications. They have been implemented to varying degrees of completeness in a computer program (BUSTER) and tested on two small structures as well as on the small protein crambin. The main obstructions to successful ab initio phasing in the latter case seem to reside in the accumulation of phase sampling errors and in the lack of a properly defined molecular envelope, both of which can be remedied within the methods proposed. A review of the Bayesian statistical theory encompassing all phasing procedures, proposed earlier as an extension of the initial theory, shows that the techniques now available in BUSTER bring closer a number of major enhancements of standard macromolecular phasing techniques, namely isomorphous replacement, molecular replacement, solvent flattening and non-crystallographic symmetry averaging. The gradual implementation of the successive stages of this 'Bayesian programme' should lead to an increasingly integrated, effective and dependable phasing procedure for macromolecular structure determination.

Journal Article↗

Sensitivity analysis of a two-dimensional probabilistic risk assessment model using analysis of variance.

This article demonstrates application of sensitivity analysis to risk assessment models with two-dimensional probabilistic frameworks that distinguish between variability and uncertainty. A microbial food safety process risk (MFSPR) model is used as a test bed. The process of identifying key controllable inputs and key sources of uncertainty using sensitivity analysis is challenged by typical characteristics of MFSPR models such as nonlinearity, thresholds, interactions, and categorical inputs. Among many available sensitivity analysis methods, analysis of variance (ANOVA) is evaluated in comparison to commonly used methods based on correlation coefficients. In a two-dimensional risk model, the identification of key controllable inputs that can be prioritized with respect to risk management is confounded by uncertainty. However, as shown here, ANOVA provided robust insights regarding controllable inputs most likely to lead to effective risk reduction despite uncertainty. ANOVA appropriately selected the top six important inputs, while correlation-based methods provided misleading insights. Bootstrap simulation is used to quantify uncertainty in ranks of inputs due to sampling error. For the selected sample size, differences in F values of 60% or more were associated with clear differences in rank order between inputs. Sensitivity analysis results identified inputs related to the storage of ground beef servings at home as the most important. Risk management recommendations are suggested in the form of a consumer advisory for better handling and storage practices.

Analysis of Variance↗

The biopsy.

The biopsy of a musculoskeletal lesion is an important event, the outcome of which guides patient management and helps determine patient prognosis. The principles of biopsy include complete radiologic staging before the biopsy, thorough prebiopsy planning including consultation with the pathologist and radiologist, determining the most appropriate method of biopsy (fine needle, core needle, open surgical biopsy), placing the biopsy tract appropriately, and making sure the biopsy tract can be removed at the time of resection, avoiding contamination of uninvolved structures, avoiding transverse incisions, preventing pathologic fracture, handling biopsy tissue appropriately, and considering referral before biopsy. The common errors of biopsy include sampling errors, postbiopsy hematomas, the use of transverse incisions, tumor implantation, and the treatment of an unsuspected sarcoma with prophylactic fixation. Thoughtful prebiopsy planning and careful completion of the biopsy can result in an expedient and accurate diagnosis. If the treating physician lacks significant expertise in performing biopsy and management of patients with musculoskeletal lesions, then referral to a musculoskeletal oncologist before biopsy should be considered.

Biopsy↗

[Cervical cancer in Frederiksborg County 1990-1991].

One hundred and eight patients from Frederiksborg County, Denmark with cervical cancer diagnosed from 1990 to 1993 were analysed concerning type of carcinoma, tumour stage and screening history. The following types of carcinoma were found: 87 (81%) squamous, 5 (5%) adenosquamous, 15 (14%) adenocarcinoma and one (1%) small cell carcinoma. All women aged 23-60 receive a written invitation to participate in the screening programme. Of the 57 patients who had never or only sporadically been screened 23 were outside the target population. Tumour stage was generally higher for the non-screened, i.e. only 57.9% stage I compared to 82.4% for the screened population. In 51 cases the following errors had occurred: seven sampling errors, 21 screening errors, 15 lack of follow-up of abnormal or inadequate smears, six inadequate cryotherapy and two interval cancers.

Adenocarcinoma↗

Comparing measurements of biomarkers with other measurements of exposure.

The issue of the relative merit of biomarkers and alternative measures of exposure arises most commonly in the context of epidemiological studies aimed at hazard detection and quantification. When exposures are from biological agents, biomarkers are usually the first and often the only justifiable choice. In general, however, the relative merit of different types of exposure measurements need to be evaluated on a case-by-case basis. Biomarkers may be affected by random errors, time-related sampling errors, physiological confounding and disease-induced differential error, all of which need to be explicitly evaluated before embarking on the use of a biomarker in a full-scale epidemiological study. Random errors affecting biomarkers may be reduced by replication or combination of measurements, or both. Alternative measurements of exposure can be evaluated against a biomarker when there is adequate evidence for regarding the marker as the true measure of a biologically relevant exposure.

Biomarkers, Tumor↗

A propagation of error analysis of the enzyme activity expression. A model for determining the total system random error of a kinetic enzyme analyzer.

We present a total system error evaluation of random error, based on a propagation of error analysis of the expression for the calculation of enzyme activity. A simple expression is derived that contains terms for photometric error, timing uncertainty, temperature-control error, sample and reagent volume errors, and pathlength error. This error expression was developed in general to provide a simple means of evaluating the magnitude of random error in an analytical system and in particular to provide an error evaluation protocol for the assessment of the error components in a prototype Miniature Centrifugal Analyzer system. Individual system components of error are measured. These measured error components are combined in the error expressiion to predict performance. Enzyme activity measurements are made to correlate with the projected error data. In conclusion, it is demonstrated that this is one method for permitting the clinical chemist and the instrument manufacturer to establish reasonable error limits.

Aspartate Aminotransferases↗

Pitfalls in epidemiological analysis.

Epidemiologists rely heavily on the relative risk in their analyses and presentations. As an index it is intelligible and intuitively appealing but can give an exaggerated impression of the strength of the association and is unreliable for comparisons. This can be shown by deriving relative risks from a normal correlation surface with an unimpressive level of correlation. Relative risks ought to be handled with caution; the underlying population risk and the relative size of exposed and reference categories should be reported. Efforts to control for additional variables, confounders, by some kind of multi-variate technique, another standard procedure, could easily give a false sense of security. From time to time it has been made clear in the literature that errors of measurement in the third variable or in the additional variables could lead to the appearance of false independent effects, but these warnings do not seem to have been heeded nearly as much as they deserve. A simulation experiment is used to bring the lesson home, with realistic numerical assumptions. A moderate degree of error contamination will produce spurious effects. This has nothing to do with sampling errors, large samples rather aggravate this danger. In meta-studies this is a source of error and conflicting results to take account of.

Confounding Factors, Epidemiologic↗