Observer error and sampling variability tested in evaluation of hepatitis and cirrhosis by liver biopsy.
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Biopsy↗
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An introduction to systematic reviews in respiratory medicine.
Reviews are an essential component of modern medicine. The volume of literature is large, even about a single treatment for pulmonary disease. The task of retrieving all the relevant papers, then assessing the evidence to reach a valid conclusion is very time consuming. At every stage there is the risk of sampling error (failure to get all the evidence) and bias (a systematic distortion of the results due to a weakness in the methodology). There are essentially two types of review: narrative reviews that follow no rules, exposing them to sampling error and bias; and systematic reviews that attempt to minimise these effects by following an explicit structure for retrieving all of the evidence and attempting an objective synthesis of the results from the different trials. A good review can serve a number of purposes including: assembling all the relevant evidence in one place, providing a valid estimate of the overall effect of treatment, producing guidance for clinical practice and generating hypotheses for further trials about patients or settings in which the treatment effect may be less or more effective.
Double-Blind Method↗
The clinical use of radionuclide bone marrow imaging.
Bone marrow aspiration and biopsy are excellent techniques for evaluating bone marrow, but this evaluation is limited to a small part of the total blood-forming organ. With the introduction of radionuclide bone marrow imaging, a simple technique became available that overcomes marrow sampling errors by giving a total body view of functioning marrow. Furthermore, the procedure is noninvasive and provides an atraumatic method for evaluating a number of clinical problems including a discrepancy between bone marrow histology and clinical status (possible marrow sampling error), the determination of amount of active marrow after radiation and chemotherapy when further therapy is being considered, detection of sites of extramedullary hematopoiesis, location of the optimal sites for bone marrow biopsy, the diagnosis and staging of diffuse hematologic disorders, detection of metastases, the diagnosis of bone marrow infarcts in hemolytic anemias, and detecting avascular necrosis of the femoral heads. There are two major classes of bone marrow agents: (1) those that are incorporated into the erythroid precursors such as radioiron and (2) colloids that are taken up by the reticuloendothelial system (RES). Indium-111 chloride was originally considered to be an erythropoietic agent but appears to share some properties of RES labels. The best label to use is dependent on the disease being evaluated.
Anemia, Aplastic↗
p53 gene status in endometrial carcinomas showing diffuse positivity for p53 protein by immunohistochemical analysis.
Although detection of p53 protein by immunohistochemical testing was originally thought to indicate p53 gene mutation, recent analyses of human malignancies have shown that high expression of p53 protein may occur without detectable gene mutation. Several explanations have been proposed for this phenomenon, including mutation out of "hot spot" regions, overexpression of wild-type protein, sampling error in molecular analyses, and conformational changes of wild-type p53 protein. As discussed, it is unlikely that the first two possibilities contribute significantly to the occurrence of this phenomenon, and the current study examined the possibility that sampling error in molecular analyses might account for a lack of concordance between immunohistochemical and molecular analyses. Such a possibility exists because immunohistochemical studies frequently report high expression when staining is only focal or regional and molecular analyses are based on the polymerase chain reaction, which is highly exponential in nature and may not detect mutation if the target gene segment is not amplified early in the chain reaction. In the current report, p53 protein expression was examined by immunohistochemical testing in 45 cases of endometrioid carcinoma, and all cases showing diffuse positivity were then examined by polymerase chain reaction in combination with single-strand conformational analysis for exons 4 to 9 with the use of a microdissection technique to separate malignant from benign cells. Of the 45 cases, diffuse staining was found in four cases, and only two of the four were found to show evidence of gene mutation.(ABSTRACT TRUNCATED AT 250 WORDS)
Base Sequence↗
Analysis of factors affecting quantification of fetomaternal hemorrhage by flow cytometry.
BACKGROUND: An analysis was carried out to determine the sources and extent of errors encountered in the quantitation of the volume of fetomaternal hemorrhage (FMH) by flow cytometry. Different assay conditions were compared, to define the simplest, most accurate protocol. STUDY DESIGN AND METHODS: D-, D+, and artificial FMH (mixtures of D+ and D- RBCs) were stained either by a direct method (using FITC-conjugated IgG3 D MoAb [BRAD-3]), with or without dual labeling with PE-conjugated anti-GPA, or by indirect methods (using polyclonal anti-D followed by FITC- or biotin-conjugated anti-IgG reagents). Cells were selected for flow cytometric analysis on the basis of either forward or side scatter (log FSC/log SSC) characteristics or of GPA+ labeling or were unselected. The numbers of events labeled with anti-D were determined from histograms. For some samples, 10 replicates of 500,000 events each were analyzed. RESULTS: Background fluorescent events in 10 directly labeled gated D- samples ranged from 0.007 to 0.023 percent, equivalent to 0.15- to 0.51-mL FMH. Both the use of a gate on log FSC/SSC or the selection of GPA+ events only resulted in a reduction in FMH of 0.3 mL or less. The intra-assay variation in FMH, or sampling error, was found to be approximately 10 percent at low artificial FMH (<10 mL) but greater (< or =50% with a CV of 15%) with D- samples. Direct staining was quicker and produced a lower background than indirect staining. CONCLUSION: The inherent sampling error that is due to the random distribution of rare events throughout the blood sample contributed greatly to the variation in the volume of FMH calculated by flow cytometry. The FMH should not be underestimated. For a routine assay, a simplified protocol and calculation will be sufficiently accurate to determine the dose of prophylactic anti-D that should be given to the patient.
Adult↗
Natural history of prostate cancer--epidemiologic considerations.
Multicentricity, heterogeneity, and sampling error complicate the study of the natural history of prostate cancer. Carcinomas previously termed "latent" are probably similar to those detected clinically. The diagnosis of carcinoma is only made following biopsy and histologic confirmation. Estimates of grade and stage made at the time of detection are prone to sampling error and are likely to change following examination of radical prostatectomy specimens. In regions with lower life expectancies, the problem of prostate cancer becomes a lower priority due to its association with aging. Access to care, numbers of medical facilities, and differing public health priorities make international rates difficult to compare. However, in view of the high worldwide prevalence of the disease, further epidemiologic studies of prostate cancer are warranted.
Adenocarcinoma↗
Cytophotometry in tumor pathology. A critical review of methods and applications, and some results of DNA analysis.
In tumor pathology the quantitation of cellular substances can be of diagnostic value. Microscope cytophotometry and digital image analysis and, on the other hand, flow cytometry are supplementary methods for measuring, each with a typical spectrum of application. The methods are predominantly used for DNA analysis: Static and image cytophotometry are applicable to cytologic and histologic slides preferably for identifying stem lines in tumors of heterogenous morphology and in merely circumscribed lesions (e.g., precancerous lesions). On the other hand, sampling errors due to preselection, and the often low number of cells actually measured, may preclude the possibility of exact cell cycle analysis. This is, in fact, an important additional option of flow cytometry resulting from the high resolution of DNA histograms, which is explained by the large number of cells that can be measured in a short period. Sampling errors in flow cytometry may result from the preparation of single cell suspensions which in certain tumor entities may suppress a varying amount of particularly fragile cells or nuclei. The prognostic significance of DNA ploidy, stem line heterogeneity and S-phase fraction is clearly described in quite a number of tumor entities. Independent of its prognostic value, the cytometric identification of stem lines might be particularly useful in the follow-up of tumor patients, where it may indicate the effectivity of systemic therapy. The development of therapeutic concepts is aptly supported by flow cytometric cell cycle analysis which helps to assess the in vitro effect of combined cytostatics on the proliferative process. Moreover, multiparameter analysis of biopsy samples may provide greater accuracy in characterising individual tumor stem lines and may furthermore help to develop improved protocols for the therapy of solid tumors.
Cytophotometry↗
Cyto-histological correlates in a colposcopic clinic: a 1-year prospective study.
As part of the Quality Assurance Program, all surgical pathology reports of cervical colposcopic biopsies, cone biopsies, and hysterectomy specimens of 772 consecutive patients were correlated with cytology results for a period of 1 yr. The abnormality in cytology or histology ranged from HPV effect to invasive carcinoma. Cytohistological correlation within one grade of severity was obtained in 662 (86%) cases. On formal review of the remaining 110 (14%) cases, sampling error occurred in 75 cytology smears and in 21 colposcopic biopsies. Screening and interpretation error occurred in 10 smears and four biopsies. In this study the sensitivity of cervical cytology in detecting epithelial abnormalities was 90%, with a positive predictive value of 99.7%. The false-negative rate of cytology was 11% and the false-positive rate 0.26%. The majority (90%) of false negatives were due to sampling error; the rest were due to laboratory error. The sensitivity of colposcopic biopsy was 97% with a positive predictive value of 99.4%. The false-negative rate of biopsy was 2.7% and the false-positive rate 0.5%. Endocervical cells were seen in 48% (370) of smears and absent in 52% (402). However, in both instances the detection rate of squamous abnormality was 90%. Also 43% (33) of smears that showed endocervical cells failed to contain the abnormal cells. Endocervical curettage or cone biopsy in 16 of these 33 cases clearly showed a small CIN-III lesion high in the endocervical canal. We believe that the value of endocervical cells as an indicator of adequacy is questionable.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Interpretation of excessive serum concentrations of digoxin in children.
Between January 1981 and April 1984, excessive serum concentrations of digoxin (5 ng/ml or higher) were recorded in 47 children, aged 2 days to 16 years. In 10 patients, the high concentrations were measured 9.25 to 48 hours after death and were significantly higher than antemortem levels in all cases (8.3 +/- 2.4 (+/- standard deviation) postmortem vs 3.3 +/- 1.5 antemortem, less than 0.0001). In 15 patients (40.5% of the living patients) serum concentrations of 5 ng/ml or higher reflected sampling errors; drug levels were monitored too closely to the administration of a dose. None of these children had toxic manifestations of digoxin. In 10 patients, the excessive concentrations were associated with renal failure and a prolonged elimination half-life (T1/2) of digoxin; in 3 of these patients, there were signs of digoxin toxicity. Six cases were caused by digoxin overdose (accidental ingestions, pharmacy error and a suicide attempt). In 6 additional cases, the existence of an endogenous digoxin-like substance (EDLS) was shown to contribute to the excessive levels of the drug. One case could be attributed to digoxin-amiodarone interaction. In 10 of 37 living patients, digoxin toxicity was diagnosed. After excluding the 15 sampling errors and 6 cases with EDLS, this represents 63% of the cases. There was a good correlation between digoxin elimination T1/2 and serum creatine concentrations (r = 0.71, p less than 0.01). The above observations suggest that excessive serum concentrations of digoxin may not necessarily reflect potentially toxic levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Cytology of treated and minimal Pneumocystis carinii pneumonia and a pitfall of the Grocott methenamine silver stain.
To clarify the role of foamy alveolar casts (FACs) in the diagnosis of Pneumocystis carinii pneumonia (PCP), we retrospectively reviewed Papanicolaou (Pap)- and Grocott methenamine silver (GMS)-stained slides from 205 bronchial specimens submitted for suspected opportunistic lung infection. FACs containing sporozoites were seen in 86 cases, all with positive GMS. FACs were absent in 119 cases with negative GMS. In patients previously treated for PCP, Pap showed FAC-like material which lacked sporozoites. GMS demonstrated clumped degenerated Pneumocystis carinii (PC) cysts. In 17 GMS-positive cases there were no FACs on Pap due to sampling error and low burden of organisms. Morphologic features of macrophages in these cases can suggest the presence of PC. When FACs are lacking, a special stain is required. When GMS is used, the control must contain PC to avoid a false negative GMS. The inconsistent uptake of GMS by PC is a pitfall which is distinct from sampling error and which to our knowledge has not been previously reported.
Bronchi↗
Extreme patterns of variance in small populations: placing limits on human Y-chromosome diversity through time in the Vanuatu Archipelago.
Small populations are dominated by unique patterns of variance, largely characterized by rapid drift of allele frequencies. Although the variance components of genetic datasets have long been recognized, most population genetic studies still treat all sampling locations equally despite differences in sampling and effective population sizes. Because excluding the effects of variance can lead to significant biases in historical reconstruction, variance components should be incorporated explicitly into population genetic analyses. The possible magnitude of variance effects in small populations is illustrated here via a case study of Y-chromosome haplogroup diversity in the Vanuatu Archipelago. Deme-based modelling is used to simulate allele frequencies through time, and conservative confidence bounds are placed on the accumulation of stochastic variance effects, including diachronic genetic drift and contemporary sampling error. When the information content of the dataset has been ascertained, demographic models with parameters falling outside the confidence bounds of the variance components can then be accepted with some statistical confidence. Here I emphasize how aspects of the demographic history of a population can be disentangled from stochastic variance effects, and I illustrate the extreme roles of genetic drift and sampling error for many small human population datasets.
Alleles↗
Fine needle aspiration diagnosis of intraabdominal and retroperitoneal lymphomas by a morphologic and immunocytochemical approach.
We reviewed 238 fine needle aspiration biopsies (FNA) of intraabdominal or retroperitoneal (IA/RP) masses in 192 patients with known or suspected lymphoma. A limited battery of immunocytochemical stains, including kappa (k) and lambda (l) light chains and Leu-4, was performed in 104 aspirates. On hundred twenty-eight of the FNA were diagnostic of or consistent with lymphoma, and three were diagnostic of carcinoma. Twenty-eight were considered negative for malignancy and 79 were suspicious for lymphoma or were nondiagnostic. For 135 of the FNA, a histologic biopsy specimen was available for comparison purposes. Overall, only one false-positive result was seen in a specimen lacking immunocytochemical data. The sensitivity of FNA lymphoma diagnosis was 66%. False-negative results due to sampling error were not uncommon, giving a predictive value of a negative result as 42%. The classification of the lymphomas by FNA was identical to that of the surgical biopsy in 86% of specimens and concurrently discrepant in 6%. We conclude that the routine performance of immunocytochemical studies on FNA of IA/RP masses is a feasible and valuable technique. Whereas suboptimal sensitivity and sampling error may make a negative diagnosis unreliable, lymphoma marker studies (combined with morphology) allow for an accurate and confident diagnosis and subclassification of lymphoma in the majority of cases.
Abdominal Neoplasms↗
Estimation and comparison of CAD system performance in clinical settings.
RATIONALE AND OBJECTIVES: Computer-aided detection (CAD) systems are frequently compared using free-response receiver operating characteristic (FROC) curves. While there are ample statistical methods for comparing FROC curves, when one is interested in comparing the outcomes of 2 CAD systems applied in a typical clinical setting, there is the additional matter of correctly determining the system operating point. This article shows how the effect of the sampling error on determining the correct CAD operating point can be captured. By incorporating this uncertainty, a method is presented that allows estimation of the probability with which a particular CAD system performs better than another on unseen data in a clinical setting. MATERIALS AND METHODS: The distribution of possible clinical outcomes from 2 artificial CAD systems with different FROC curves is examined. The sampling error is captured by the distribution of possible system thresholds of the classifying machine that yields a specified sensitivity. After introducing a measure of superiority, the probability of one system being superior to the other can be determined. RESULTS: It is shown that for 2 typical mammography CAD systems, each trained on independent representative datasets of 100 cases, the FROC curves must be separated by 0.20 false positives per image in order to conclude that there is a 90% probability that one is better than the other in a clinical setting. Also, there is no apparent gain in increasing the size of the training set beyond 100 cases. DISCUSSION: CAD systems for mammography are modeled for illustrative purposes, but the method presented is applicable to any computer-aided detection system evaluated with FROC curves. The presented method is designed to construct confidence intervals around possible clinical outcomes and to assess the importance of training set size and separation between FROC curves of systems trained on different datasets.
Algorithms↗
An assessment of DHS maternal mortality indicators.
This study presents an assessment of the quality of data relating to maternal mortality collected in 14 Demographic and Health Surveys (DHS) for 13 countries that included a complete sibling history. Four aspects of data quality are considered: completeness of the data for reported events, evidence of omission in the reporting of events, plausibility of the pattern of sibling deaths, and sampling errors of the maternal mortality estimates. Although the data relating to reported events are complete for most variables, comparisons of sibling-history-based estimates of adult mortality for both males and females with other independent estimates suggest that sibling estimates are more likely to be underestimates than overestimates. The downward bias is probably greater for female mortality than for male mortality. The sampling errors associated with maternal mortality ratios are substantially larger than those associated with other frequently used DHS indicators. This lack of precision precludes the use of these data for trend analysis and has led to the recommendation that this DHS module not be used more than once every ten years in the same country.
Adolescent↗
Fine-needle aspiration biopsy of bronchioloalveolar carcinoma.
BACKGROUND: The purpose of the current study was to determine the accuracy of the cytologic diagnosis of bronchioloalveolar carcinoma (BAC) by fine-needle aspiration biopsy (FNAB). METHODS: During a 4-year period (1994-1998), 1664 lung FNABs were performed. Forty-nine patients with BAC diagnosed by FNAB and/or surgical biopsy formed the basis of this study. RESULTS: Twenty-four patients diagnosed with BAC by FNAB had histologic confirmation. Surgical pathology revealed BAC in 15 patients with a cytologic diagnosis of large cell carcinoma (LCA) or adenocarcinoma (ACA). Nine patients diagnosed with BAC by FNAB were found to have ACA histologically. One unsatisfactory aspirate was diagnosed as BAC by surgical pathology. Review of 15 FNAB specimens with a diagnosis of LCA or ACA revealed cytologic features typical of BAC. In six aspirates, additional features such as pronounced nuclear crowding and overlapping, variation in nuclear size, and increased number of pleomorphic cells interfered with the FNAB diagnosis of BAC. Nine FNABs with a diagnosis of BAC were found histologically to have ACA with a focal BAC growth pattern. One unsatisfactory FNAB aspirate diagnosed as BAC histologically was due to sampling error. CONCLUSIONS: A diagnosis of BAC by FNAB is possible using conventional cytologic criteria. Some BACs show pronounced nuclear crowding and overlapping, variation in nuclear size, and an increased number of pleomorphic cells cytologically, which may interfere with an FNAB diagnosis of BAC. FNABs from ACA cases with a focal BAC pattern remain a diagnostic dilemma due to the nature of the lesion. In addition, sampling error by FNAB can be a diagnostic pitfall. Cancer (Cancer Cytopathol)
Adenocarcinoma, Bronchiolo-Alveolar↗
Tutorial reduces protocol deviations in multicenter ACTG trials with pharmacology endpoints.
PURPOSE: The AIDS Clinical Trials Group (ACTG) pharmacology quality assurance program requires clinical research staff to demonstrate minimum competencies in clinical pharmacology research. To achieve this goal, a tutorial was designed to improve the accuracy and completeness of data collected in ACTG pharmacology protocols. METHOD: Clinical research staff at AIDS Clinical Trials Units (ACTUs) access the tutorial through the network's Website. The tutorial presents pharmacokinetic study concepts by contrasting poor with perfect study conduct to illustrate the influence of data quality on conclusions. Case report forms and laboratory data were audited retrospectively to examine the pre- and posttutorial incidence of targeted errors. RESULTS: During a 2-year period, 236 study nurses at 64 main and subunit ACTUs completed the tutorial. The percentage of visits with dosing and/or sampling errors dropped from 13% to 4%. The percentage of samples with errors decreased from 6% to 3%. Sample-time errors (blood drawn outside of the 15-minute target time) decreased slightly, from 2.9% to 2.4%, but the discrepancies found in the recording of sample times decreased from 3% to <1%. CONCLUSION: The ACTG clinical pharmacology tutorial program improved accuracy of both protocol conduct and data collection for pharmacology objectives.
Acquired Immunodeficiency Syndrome↗
Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach: a reality or merely an hypothesis?
The results of recent investigations have suggested that the old hypothesis of an atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach needs to be qualified. The most common cause of intestinal metaplasia is Helicobacter pylori gastritis. The consequence of this intestinal metaplasia is focal atrophy. Helicobacter pylori infection may also trigger an autoimmune gastritis of the corpus mucosa, with atrophy and intestinal metaplasia. Most intestinal metaplasias are only 'paracancerous' but not 'precancerous' lesions. Diffuse gastric carcinomas, such as the signet ring cell carcinoma, arise independently of intestinal metaplasia. Histogenetically, numerous carcinomas of the stomach are primarily of the gastric type, and may secondarily change into the intestinal type.High-grade intra-epithelial neoplasias (dysplasias) detected during the biopsy-based diagnostic work-up appear to be a marker for carcinoma and must, therefore, be removed endoscopically. The detection of intestinal metaplasia in routinely obtained biopsy material is subject to sampling error and is, therefore, not a suitable marker for an increased risk of a gastric carcinoma developing. As an alternative, the concept of gastritis of the carcinoma phenotype, which is more frequently found in early gastric carcinomas and in the relatives of gastric carcinoma patients, has been developed. In this concept, the diffuse parameters of grade and activity of the gastritis in the antrum and corpus, which are independent of sampling error, are subjected to a comparative analysis. A risk gastritis of the carcinoma phenotype is diagnosed when the grade and activity of the gastritis in the corpus are at least equally as pronounced as in the antrum. Currently, this concept is being tested in a prospective ongoing study. Future studies must show whether, and if so which, immunohistochemical or molecular-genetically detectable changes can be applied as risk markers in the diagnostic work-up. Helicobacter pylori eradication probably does not lead to complete regression of the intestinal metaplasia and ensuing focal atrophy. However, eradication of H. pylori does lead to the normalization of changes that can lead to mutations of the stem cells of the gastric mucosa (free radicals, nitric oxide, cell proliferation and vitamin C secretion).
Gastric Mucosa↗
National Survey of Family Growth: design, estimation, and inference.
The purpose of this report is to document the procedures used in the 1988 National Survey of Family Growth (NSFG) to select the sample, weight the data to produce national estimates, impute missing data, and estimate sampling errors. Therefore, this report necessarily contains a great deal of technical detail. For readers who do not need this level of detail, this summary briefly describes the procedures used. The National Survey of Family Growth is conducted every few years by the National Center for Health Statistics (NCHS), a part of the U.S. Department of Health and Human Services. The purpose of the survey is to collect and publish data from a national sample of women on childbearing, factors affecting childbearing (such as contraception, sterilization, and infertility), and related aspects of maternal and infant health. Interviewing for Cycle IV of the survey was done in 1988 by Westat, Inc., under a contract with NCHS. Personal interviews were conducted between January and August of 1988 with a national sample of 8,450 women in the civilian noninstitutionalized population of the United States. Interviews were conducted in person by trained female interviewers and lasted an average of 70 minutes. The interview focused on the woman's pregnancies, if any; her use of contraception; her ability to bear children (fecundity and infertility); her use of medical services for family planning, infertility, and prenatal care; her marriage and cohabitation history, if any; and a wide range of demographic and economic characteristics. This report describes some of the main methodological aspects of the survey, including the sample design, weighting, sampling errors, and imputation of missing data. These topics will be described briefly and less technically in this summary. Each topic is discussed in more detail in the rest of the report.
Adolescent↗