CLIN. CHEM. 31/5, 746-750 (1985) flexible gas chromatograph-masspectrometer-computer search systemto identify drugs and their metabolites in body fluids of overdosevictims. Clin Chem 20, 255-265 (1974). 17. FinkleBS, Foltz RL, Taylor DM. A comprehensive CC-MS reference data systemfor toxicological and biomedical purposes. J Chromatogr Sci 12, 304-328 (1974). 18. Foltz RL. Mass spectrometry. Op.cit. (ref. 9), pp 1-30.

BACKGROUND:Elevated concentrations of homocyst(e)ine are thought to increase the risk of vascular diseases including coronary heart disease and cerebrovascular disease. METHODS:We searched MEDLINE (1966-1999), EMBASE (1974-1999), SciSearch (1974- 1999), and Dissertation Abstracts (1999) for articles and theses about homocyst(e)ine concentration and coronary heart disease and cerebrovascular disease. RESULTS:We included 57 publications (3 cohort studies, 12 nested case-control studies, 42 case-control studies) that reported results on 5518 people with coronary heart disease (11,068 control subjects) and 1817 people with cerebrovascular disease (4787 control subjects) in our analysis. For coronary heart disease, the summary odds ratios (OR) for a 5-micromol/l increase in homocyst(e)ine concentration were 1.06 (95% CI : 0.99-1.13) for 2 publications of cohort studies, 1.23 (95% CI : 1.07-1.41) for 10 publications of nested case-control studies, and 1.70 (95% CI : 1.50-1.93) for 26 publications of case-control studies. For cerebrovascular disease, the summary OR for a 5-micromol/l increase in homocyst(e)ine concentration were 1.10 (95% CI : 0.94-1.28) for 2 publications of cohort studies, 1.58 (95% CI : 1.35-1.85) for 5 publications of nested case-control studies, and 2.16 (95% CI : 1.65-2.82) for 17 publications of case-control studies. CONCLUSIONS:Prospective studies offer weaker support than case-control studies for an association between homocyst(e)ine concentration and cardiovascular disease. Although other lines of evidence support a role for homocyst(e)ine in the pathogenesis of cardiovascular disease, more information from prospective epidemiological studies or clinical trials is needed to clarify this role.

Dried blood spots (DBSs) are used to screen newborns for phenylketonuria and other aminoacidopathies. The calibrators for this testing are usually DBSs with values for Phe. Two DBS reference materials have been prepared, the European Working Standard for Phe (EWS-Phe-01) (1) and the amino acid reference material (AARM) from the CDC (2). The two reference materials are not interchangeable because they differ in blood hematocrit, blood-spot size, and filter paper, each of which (3)(4)(5)(6) affects analyte recovery. We measured quantitatively the effects of these differences on analyte recovery from DBSs and used results from our measurements to predict expected Phe recoveries from tandem analyses of the two sets of materials. In EWS-Phe-01 (1)(7), human blood with a 50.5% hematocrit and intact red cells was divided into five portions for enrichment with 0, 20, 40, 80, and 120 mg Phe/L blood (0, 120, 240, 480, and 720 μmol/L blood). The liquid added during enrichment (7) was sufficient to reduce the hematocrit to 50.1%. The Phe-enriched blood portions were dispensed in 35-μL aliquots (7) onto Schleicher & Schuell (S&S) Grade 2992 (lot no. 121576) filter paper (1). The AARM was prepared (2) by dividing human blood with a 57% hematocrit and intact red cells into six portions for enrichment with pure amino acids to cover the usual analytic ranges of Phe, Tyr, Leu, Met, and Val. The Phe enrichments were 0, 40, 80, 120, 160, and 200 mg Phe/L blood (0, 240, 480, 720, 960, and 1200 μmol/L blood). The liquid added during enrichment was sufficient to reduce the hematocrit to 53%. The whole-blood pools were dispensed in 100-μL portions onto S&S Grade 903 (lot no. W941) filter paper with dashed-line 13-mm printed circles (2). To examine the effect of blood hematocrit …

Background. The WISEWOMAN projects are examining the feasibility and effectiveness of adding a cardiovascular disease (CVD) prevention component to a nationwide program of early detection for breast and cervical cancer aimed at financially disadvantaged women. This paper describes the rationale and design of the WISEWOMAN projects, the baseline findings of the screenings, and the plans for evaluation. Methods. In selected breast and cervical cancer screening sites throughout Massachusetts, Arizona, and North Carolina, blood pressure, body weight, cholesterol, smoking, diet, and physical activity were assessed at baseline, 6 months, and 12 months. To evaluate the effectiveness of CVD prevention, these sites were assigned to either a minimum or an enhanced intervention group. The enhanced interventions, tailored to the populations served, featured skill building and facilitating activities to improve nutrition and increase physical activity. Results. Baseline screenings of 4,842 women revealed a high prevalence of CVD risk factors. High cholesterol was found among 40% of the women in North Carolina and Massachusetts, hypertension was found among 63% of the women in North Carolina, and overweight was found among 83% of the women in Arizona. Conclusions. It is appropriate to expand breast and cervical cancer screening programs to include screening for CVD. (C) 1999 American Health Foundation and Academic Press.

BACKGROUND:Advances in technology and the earlier release of newborns from hospitals have pressed the demand for accurate calibration and improved interlaboratory performance for newborn screening tests. As a first step toward standardization of newborn screening aminoacidopathy tests, we have produced six-pool sets of multianalyte dried-blood-spot amino acid reference materials (AARMs) containing predetermined quantities of five amino acids. We describe here the production of the AARMs, validation of their amino acid contents, and characterization of their homogeneity and their stability in storage.METHODS:To each of six portions of a pool of washed erythrocytes suspended in serum we added Phe (0-200 mg/L), Leu (0-200 mg/L), Met (0-125 mg/L), Tyr (0-125 mg/L), and Val (0-125 mg/L). Six-pool sets (1300) were prepared, dried, and packaged. We used isotope-dilution mass spectrometry to estimate the endogenous amino acid concentrations of the AARMs and validate their final amino acid concentrations. We used additional tandem mass spectrometry analyses to examine the homogeneity of amino acid distribution in each AARM, and HPLC analyses to evaluate the stability of the amino acid contents of the AARMs.RESULTS:The absolute mean biases across the analytic range for five amino acids were 2.8-9.4%. One-way ANOVAs of the homogeneity results predicted no statistically significant differences in amino acid concentrations within the blood spots or within the pools (P >0.05). Regression slopes (0 +/- 0.01) for amino acid concentrations vs storage times and their P values (>0.05) showed no evidence of amino acid degradation at ambient temperatures, 4 degrees C, or -20 degrees C during the intervals tested.CONCLUSION:The validation, homogeneity, and stability of these blood spots support their use as a candidate national reference material for calibration of assays that measure amino acids in dried-blood spots.

BACKGROUND:Detection of cobalamin deficiency is increasingly important, and methylmalonic acid (MMA) appears to be a useful marker. Information on interlaboratory variation and on methodological differences for MMA in serum and plasma is limited.METHODS:Using gas chromatography/mass spectrometry, 13 laboratories participated in a 2-day analysis of 8 serum and 11 EDTA-plasma specimens. Results were analyzed for imprecision, recovery, and differences among laboratories and methods.RESULTS:The mean among-laboratory imprecision (CV) was 19% and 21% for serum and plasma samples, respectively, and 9.3% and 7.8% for serum and plasma samples with added MMA, respectively. The mean within-laboratory (among-run) CV was 13% for both serum and plasma samples and 5.2% and 4.9% for serum and plasma samples with added MMA. Within-method imprecision was the same or higher than among-method imprecision. The mean among-laboratory recovery of MMA was 105% and 95% in serum and plasma, respectively. Most laboratories showed a proportional bias relative to the consensus mean of up to 15%. Two laboratories reported results that on average were almost 30% higher than the consensus mean.CONCLUSIONS:No method differences were found, but significant among-laboratory imprecision was found in the present study. Improvements are needed to reduce the analytical imprecision of most laboratories, and attention must be focused on calibration issues. Differences among laboratories can be improved by introducing high-quality reference materials and by instituting external quality assessment programs.

Statistics in MedicineVolume 15, Issue 18 p. 1985-1986 Article Close of symposium S. Jay Smith, S. Jay SmithSearch for more papers by this author S. Jay Smith, S. Jay SmithSearch for more papers by this author First published: 30 September 1996 https://doi.org/10.1002/sim.4780151810AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume15, Issue1830 September 1996Pages 1985-1986 RelatedInformation

Using data from a meta-analysis of the effects of oestrogen replacement therapy on the development of breast cancer, we compared alternative methods for combining dose-response slopes from epidemiological studies. We evaluated issues related both to summarizing data from single studies and to combining results from multiple studies. Findings related to the analysis of individual dose-response studies include: (1) a method of weighing studies that gives greater influence to dose-response slopes that conform to the linear relation of relative risk to duration can lead to large differences in calculated weights as a function of non-linearity; (2) a regression model using a variable-intercept resulted in a mean dose-response slope that increased as much as threefold when compared with the values obtained with a zero-intercept model. When combining results from multiple studies, we found: (1) calculating standard errors of mean dose-response slopes by methods that allow for both among-study and within-study variability (a random-effects type model) gave values different from a method that assumes homogeneity and equal within-study precision (a fixed-effects model); (2) the random-effects model gives mean and standard error results most similar to a bootstrap resampling method as increasing heterogeneity is observed (however, this model could give biased mean estimates compared with the bootstrap method); (3) a components-of-variance model compares favourably with the bootstrap and is easier to apply than the random-effects model. Based on these findings, we recommend the use of methods which incorporate heterogeneity to guard against underestimating the standard error. However, caution is urged because bias in point estimates can occur if extreme heterogeneity is present. Two other observations affect the interpretation of data combined from multiple studies. First, inclusion into a model of quality scores assigned by blinded reviewers had little effect on the mean dose-response slope and its standard error. Second, the number of studies required to achieve desired statistical power, varies with effect size.

Recent meta-analyses of studies of the risk of breast cancer associated with hormone replacement therapy agree that little risk is associated with ever-use or short-term use of estrogen replacement. These analyses disagree, however, about the effect of long-duration estrogen use. To understand differences in the findings among the meta-analyses of the effect of long-term use, we investigated the source of heterogeneity among the included studies. We analyzed subgroups by source of controls (community vs hospital), study design (case-control vs follow-up), and types of estrogen. We also examined the effect of modeling assumptions: that before women began estrogen use, those who chose to use estrogen replacement (1) were, or (2) were not, at substantially different risk from those who chose not to use estrogen. We found a small increase in risk in all subgroups of studies except those that used hospital controls. From a homogeneous group of case-control studies using community controls that analyzed the effect of conjugated equine estrogens, we estimated that the risk of breast cancer after 10 years of estrogen use increased by at least 15% and up to 29%.

Since scientists recognized that preanalytical sources of variation often constitute more than 60% of the total variation in reported lipid measurements, they have been concerned about both the effects of these sources and ways to minimize their impact on lipid measurement. Sampling techniques, behavioral factors, metabolic disorders, and disease status are major preanalytical sources of variation. Lipid analysis of serial specimens from one person can minimize the effect of preanalytical sources on the reported lipid test result. A procedure using relative range can determine the number of specimens needed to assure that the total intraindividual coefficient of variation is <5.0%.

Immunophenotyping of different lymphocyte populations was carried out in parallel on 113 consecutively received specimens of human peripheral blood using 2 different data acquisition and analysis systems (EPICS C and 4Cyte-Acmecyte) on the same flow cytometer (EPICS C). The phenotypes analyzed were CD3+, CD4+, CD8+ CD56+ CD16+ CD3-, TCR-gamma delta+ CD8-, and TCR-gamma delta+ CD8+. Both HIV- and HIV+ specimens were used for this study, including some with CD4 levels as low as 2% of all lymphocytes. Despite differences in gating procedures and shapes of bitmap (rectilinear vs. "amorphous"), the 2 methods agreed to within 2% positive cells in 97% of the cases. Although some statistically significant biases in the methods were observed, these were small and not biologically important. We conclude that both methods of data acquisition and analysis, as employed by experienced operators on the EPICS C flow cytometer, gave essentially equivalent results for lymphocyte sub-populations in peripheral blood preparations.

We present the results of an evaluation of the performance characteristics of a composite multivariate quality control (CMQC) system that incorporates quality control rules for univariate, multivariate, and correlation conditions. The CMQC system evaluated is designed to help analysts detect unacceptable trends and systematic error in one or more variables, unacceptable random error in one or more variables, and unacceptable changes in the correlation structure of any pair of variables. It is also designed to be tolerant of missing data, to allow analysts to reject as few as one or as many as all variables in a run, and to provide analysts with control statistics and graphics that logically relate to sources of analytical error. We show that the various components of the CMQC system have adequate statistical power to detect systematic errors, random errors, and correlation changes under the conditions likely to be encountered with multivariate analytical measurement systems: (1) a single variable with increased systematic or random error; (2) all variables or a subgroup of variables affected by a common problem that increases systematic or random error; and (3) missing data for one or more variables in a run. We also show that the power of the multivariate component of the CMQC system to detect systematic and random errors is higher than the power of an alternative multivariate test criterion.

We propose a composite multivariate quality control (CMQC) system to control simultaneously measured variables. This system is designed to detect unacceptable trends and systematic error in one or more variables, unacceptable random error in one or more variables, and unacceptable changes in the correlation structure in any pair of variables. It is also designed to be tolerant of missing data, to be capable of rejecting as few as one or as many as all variables in a run, and to provide the analyst with control statistics and graphics that logically relate to sources of analytical error. Quality control rules for univariate, multivariate, and correlation conditions are incorporated in the system, as are plots displaying CMQC statistic values and control limits for univariate, multivariate, and correlation parameters. We also discuss advantages of the CMQC over the T2 and principal component multivariate quality control methods. We demonstrate the CMQC procedure using data from a laboratory process in which 40 variables were measured during 40 characterization runs and 23 runs analyzing unknowns.

Urine samples from 197 Arkansas children were analyzed for eight chlorinated phenols and four chlorinated phenoxy herbicides by using a new procedure that combined gas chromatography with tandem mass spectrometry. With the detection limit of 1 part per billion (ppb), six of these pesticides were detected in more than 10% of the samples. 2,5-Dichlorophenol (a metabolite of p-dichlorobenzene), and pentachlorophenol were detected in 96% and 100%, respectively, of the children's urine at median concentrations of 9 ppb and 14 ppb, respectively. 2,4,5-Trichlorophenol was detected in 54% of the children's urine at a median concentration of 1 ppb. One trichlorophenol and three other dichlorophenols were found in 3% to 27% of the samples. The herbicide 2,4-dichlorophenoxyacetic acid was observed in 20% of all samples. The concentrations of all analytes are reported as background or reference levels for use in future studies. The finding of 2,5-dichlorophenol as a ubiquitous contaminant merits further study.

The Centers for Disease Control (CDC), in collaboration with the National Heart, Lung and Blood Institute, has supported programs for standardization of lipid measurements for more than 30 years. The cornerstone of these lipid standardization programs has been an accuracy base of lipid reference materials and methods developed by the CDC. Through its efforts with manufacturers of diagnostic products and specialized lipid research laboratories, CDC′s standardization programs have become a national resource for improving accuracy in the measurement of cholesterol and other lipids, lipoproteins, and apolipoproteins.

Using data from the National Health and Nutrition Examination Survey (NHANES II) 1976-1980, we demonstrate how cross-sectional total serum cholesterol surveillance data can be used by an individual to assess current and future personal cholesterol risk status. We propose statistical models, based on a person's current measured cholesterol level and the relationship between cross-sectional age and cholesterol percentile estimates, that will allow prediction of future cholesterol levels or the age at which specified cholesterol risk levels will be reached if no cholesterol-altering intervention is taken. These models incorporate the observed variation in the NHANES II data and expected intraperson biological variation and intralaboratory analytical variation. We illustrate the adequacy of the models using data from the longitudinal Framingham Study.

Five-month-old female Sherman rats were dosed by gavage with 0 or 500 mg of Firemaster BP-6 (polybrominated biphenyls, PBBs) per kg body weight as a 5% solution in corn oil and then maintained on normal diet and waterad libitum. Urine pools from test and control groups of five fasting rats were collected once a month, up to 179 days after the test rats were dosed. PBB-dosed animals showed significantly higher (p=0.0003) creatinine-corrected proteinuria. Two-dimensional electrophoresis (2DE) and silver staining were used to determine differences in urinary protein patterns between test and control rats. Dosed animals excreted new proteins with higher molecular weight and more basic isoelectric points than controls. The appearance of numerous, new proteins excreted by the PBB-dosed rats demonstrates the utility of 2DE for the sensitive detection of possible health effects from toxicant exposure.

In 1971, 2,3,7,8-tetrachlorodibenzodioxin (TCDD)-containing waste oils were sprayed for dust control on residential, recreational, and work areas in Missouri. In several of these areas, the magnitude and the extent of this environmental contamination were not known until late 1982 or 1983. In the first phase of the investigation, a group of persons considered to be at highest risk of exposure and an appropriate comparison group were selected from reviews of Health Effects Survey screening questionnaires. These persons received complete medical examinations and a series of laboratory tests focused on detecting presymptomatic effects in key target organ systems (i.e., hepatic, dermatologic, immunologic, and neurologic effects). Comparisons of these two groups did not produce any firm indications of increased disease prevalence directly related to the putative exposures; of significance is the fact that no cases of chloracne or porphyria cutanea tarda were seen. Nevertheless, no overall definitive conclusion should be based just on this initial pilot study. Insights were provided that are being examined in more refined epidemiologic studies using different designs and strategies--especially of larger, more homogeneous population groups in which exposure status can be better characterized--focused primarily on discerning any potential effects on the urinary tract, liver, neurological, and immune systems. Concurrently, research into the development of replicable laboratory analytical methods and reference ranges for measuring TCDD body burden are being pursued.