Desirable performance standards for assays of serum water and osmolality.
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Biomedical subjects
Publications and source records attributed to C G Fraser.
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We evaluated the analytical performance of the Du Pont Dimension Clinical Chemistry System to assess its suitability as a replacement for the Du Pont aca III, currently routinely used for analysis of pediatric, high-risk, and emergency specimens. Twenty-six analyses were studied. These generally fulfilled pre-set analytical goals for precision based on biological variation or "state of the art." Significant economies were achieved and we found the Dimension to be reliable, easy to operate, and simple to maintain. It also fulfilled safety requirements for analysis of specimens of high risk to laboratory staff.
Few analytic goals have been proposed for hematology tests, and these are based upon subjective clinical opinions. It is proposed that the current consensus strategies for delineating analytic goals in clinical chemistry can be validly used in the other disciplines of clinical pathology. Goals for imprecision are best based upon average intraindividual biologic variation; such goals are more stringent than those previously published. There are many cogent reasons that justify the goal for inaccuracy of no bias. In consequence, goals for imprecision should be viewed as goals for total laboratory error. Further experimental work on biologic variation is required to develop a wider range of goals for hematology and coagulation tests, if these strategies are considered worthy of adoption.
Studies of the effectiveness of various strategies for influencing clinicians' test-requesting behaviour are reviewed. Numerical rationing, although crude, effectively reduces unnecessary repeat testing without detriment to patient outcome. Educational programmes involving peer review show pronounced but short-lived effects. Simple feedback of information about numbers of tests requested and their costs is surprisingly ineffectual. Direct financial incentives, in a private health care system, also failed. Clinical budgeting, of benefit in experimental trials, has yet to be widely tested, and the savings on reducing laboratory requesting may not be large enough to be attractive to clinicians. Agreed requesting policies in various specialties and clinical circumstances, endorsed by senior clinicians and prestigious professional bodies, seems a promising approach to more appropriate test requesting; further objective studies of their long-term effects are needed. Redesign of request forms into a problem-orientated format may be the simplest and most effective contribution by the laboratory; this strategy deserves further critical appraisal.
Analytical, intra-individual, and interindividual components of variation have been determined for pH, pCO2, bicarbonate, base excess, and total CO2 in capillary specimens of whole blood from a cohort of 14 healthy subjects. Calculated analytical goals (SD) are pH less than or equal to 0.008, pCO2 less than or equal to 0.9 mmHg, bicarbonate less than or equal to 0.5 mmol/L, base excess less than or equal to 0.5 mmol/L, and total CO2 less than or equal to 0.5 mmol/L. Because pH and base excess vary little between individuals, population-based reference values for them will be of utility in interpretation of results; pCO2, bicarbonate, and total CO2 show more marked variation between individuals, and reference values for them will be of more limited use. The generally applicable differences required for two results to be significantly different (P less than or equal to 0.05) when goals are met--which is currently feasible--are pH: 0.04, pCO2: 0.745 kPa (5.6 mmHg), bicarbonate: 2.6 mmol/L, base excess: 2.2 mmol/L, and total CO2: 2.7 mmol/L.
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Analytical, intra-individual, and interindividual components of variation for sodium, potassium, urea, creatinine, calcium, and phosphate were estimated from results for 24-h urine specimens collected from 15 apparently healthy individuals every four weeks for 40 weeks. Expressed as output, mean values differed for men and women, except for calcium. Our data on intra-individual variation were similar to those obtained for 10 men by Shephard et al. (Clin Chem 1981;27:569-73). Calculated analytical goals are easily attained by current methods. Reference values for urine creatinine are useful only when expressed as output and stratified according to gender. The ratios of intra- to interindividual variation generally increase on such stratification; separate reference values for men and women are therefore required for analytes expressed as output. Measurements of sodium and potassium in urine should be reported as concentration, but output terms are favored for the other analytes. Differences for two serial results from an individual must be rather large to differ statistically.
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We describe a method for measuring plasma, erythrocyte, and leukocyte sodium (Na+), potassium (K+), and magnesium (Mg2+) concentrations in 10-mL blood specimens. After separating cells with Ficoll-Hypaque and washing with isotonic choline chloride, erythrocytes and leukocytes are counted, so that results can be expressed as amount of substance per cell and also to monitor cell integrity and possible contamination. Plasma and cell lysates were analyzed (CV less than or equal to 7.0%) with flame photometry and atomic absorption spectrometry. Reference intervals for an elderly population with values for plasma electrolytes within reference intervals are similar to those for younger healthy subjects. From data on biological variation, reference values for erythrocyte cations are not of much use, and analytical goals for precision are not met, but the results might be useful for monitoring disease progression in individual patients. In contrast, reference values for leukocyte cations are theoretically of use and goals are achieved, but large changes are required before consecutive results can confidently be said to be significantly different.
The time interval between collection of specimens from an individual patient is usually determined empirically. For analytes whose values decline according to first-order kinetics--for example, enzyme activities in serum after an acute myocardial infarction, tumor markers in serum after excision of the tumor, and drugs in serum after an overdose--the minimum time between collections (delta T) depends on the elimination half-life (t) and the analytical precision (CVA), according to the equation: delta T = (1/log2) X t X log (2.33 CVA/100 + 1). Nomograms showing this relationship graphically have been generated.
To investigate the optimum specimen for quantifying low, but abnormal, concentrations of albumin in urine, we assessed the analytical and biological components of variation in first morning, random untimed, and 24-h urine specimens from 11 apparently healthy individuals. The results were expressed in terms of albumin concentration, albumin/creatinine ratio, and albumin excretion rate. Analytical methods generally can meet the analytical goal of CV less than or equal to 18%. For reasons detailed herein, we prefer measurement of the albumin concentration in the first morning specimen. Expressing results as an albumin/creatinine ratio has little advantage. Albumin concentrations in first morning urines from 16 diabetic subjects showed larger intra-individual variation than for nondiabetic subjects but clearly fell into two groups: those with consistently normal albumin concentrations in urine and those with abnormal concentrations in some specimens. The intrinsic biological variation of the latter group means that the ideal 100% nosological specificity cannot be achieved with any cutoff point without inclusion of a large proportion of the former. Qualitative testing with a latex-agglutination technique also demonstrates this problem. Use of data on biological variation allows development of an appropriate clinical strategy to investigate diabetic patients.
Methodological problems with the assay of fructosamine in serum--standardization, matrix effects, and dependence on buffer pH--have been minimized with a method involving colorimetric assay of each specimen and subsequent re-assay after standard addition of 1-deoxy-1-morpholinofructose. Absorbance at optimum wavelength of 540 nm varies linearly with fructosamine concentration to at least 5.5 mmol/L, and between-run precision is about 6% for both patients' specimens and quality control materials. Correction of fructosamine to serum albumin of 40 g/L minimizes the effect of albumin while maintaining transferability of data and reference values. From data on biological variation, the analytical goal for precision (CV) is less than or equal to 2.6%. The square root of the ratio of intra- to interindividual variance is low, indicating that fructosamine concentrations have a high index of individuality; thus conventional population-based reference values are of limited use. Although this assay may be useful in monitoring disease, we doubt that it provides a valid screening test for diabetes.
Therapeutic drug monitoring is an important aspect of clinical chemistry for which no objective analytical goals yet exist. Based on fundamental pharmacokinetic theory, and the current consensus strategy for analytical goal-setting for precision based upon biological variation, a theoretical model allows derivation of the goal that: analytical CV less than or equal to 1/4 [(2T/t - 1)/(2T/t + 1)] X 100%, where T is the time interval between doses, and t is the average elimination half-life. Using published data on half-lives, I have derived goals for analysis for (e.g.) digoxin, lithium, some antiepileptic drugs, and theophylline. The goal for accuracy proposed is that methods should have no bias and should generate true values. Goals for precision should therefore be viewed as goals for total analytical error.
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