The assessment of interpretation in clinical biochemistry: a personal view.

In many laboratories, clinical biochemists add interpretative comments to laboratory reports. There is, however, little evidence base to support this activity. Interpretative comments attached to reports are quite complex, usually consisting of several components that may suggest possible diagnoses and additional tests. Every comment is different, and assessment of interpretation is difficult. We illustrate different approaches which can be used: assessing whole comments or comment components or key phrases; and using independent assessors or a pooled panel of experts. No approach has yet been optimized: assessment is a guide to and not a definition of exact solutions. Although External Quality Assurance Schemes examining interpretation provide information to individual participants on how their comments compare with others, a more important role of these Schemes is to enable us to pool knowledge, and their primary purpose is educational.

Provision of interpretative comments on biochemical report forms.

Providing interpretative comments on reports, particularly those for primary care physicians is an important part of our job. Few clinical biochemists (whether medical or scientific) receive significant training for this. Most work in isolation, and few receive feedback on the utility of their comments. Surveys show an extremely wide divergence of opinion and comment even on apparently straightforward sets of abnormal results. Some comments are regarded as highly inappropriate when assessed by peer review. There is a need for further education and training in this area, concentrating as much on 'how to comment' as on 'what to comment'. There is also a need to establish some form of quality assurance for this important part of the post-analytical phase. A pilot External Quality Assurance Scheme (EQAS) is now being established.

Experience with assessing the quality of comments on clinical biochemistry reports.

We assess a previously described scoring system for the appropriateness of interpretative comments on clinical biochemistry reports over 21 distributed cases and over a group of 41 UK-based participants. The distributed cases covered a range of clinical scenarios and included pre- and post-analytical problems. The UK-based participants had all registered an interest in using this case participation for their continuing professional development; all had higher professional qualifications in clinical biochemistry, and the group included participants based in teaching hospitals and district general hospitals as well as those with a medical or a scientific background. Although the present scoring system favours participants who mention more than one possible outcome and who include several ideas for further investigation, its advantages seem to outweigh its disadvantages. The scored cases are currently unique, and are seen to be of major educational value not only by active participants but also by those who are using them for teaching or in discussion groups.

Assessing the quality of comments on reports: a retrospective study.

I describe a comparatively simple method for assessing the quality of comments on clinical biochemistry reports. It is based on independent peer review of components of comments, appears reasonably robust and correlates well with separate independent assessment of the value of complete comments. The method gives a numerical score, and thus lends itself to a wide range of statistical manipulations and assessment for education and audit purposes.

Effect of hemicholinium-3 on the hypothalamic concentration of a cytochemically detectable glucose-6-phosphate dehydrogenase-stimulating substance.

Hypothalamus and plasma of salt-loaded rats, spontaneously hypertensive rats (SHR), and hypertensive reduced renal mass rats (RRM), and the plasma of patients with essential hypertension and of Milan hypertensive rats contain an increased concentration of a cytochemically detectable glucose-6-phosphate dehydrogenase (G6PD)-stimulating substance that has properties similar to that of a possible choline derivative di-methyl methylene immonium ion. Intracerebroventricular (i.c.v.) administration of hemicholinium-3 (HC-3) selectively blocks high-affinity neuronal choline uptake, inhibits brain acetylcholine (ACh) synthesis, and decreases arterial pressure in SHR through an inhibiting effect on hypothalamic cholinergic function. The experiments were performed to study the effect of centrally administered HC-3 on the content of the cytochemically detectable cholinelike substance in hypothalamus and plasma of SHR. HC-3 or saline was infused into the lateral cerebral ventricle for 6 days with a minipump in 14 SHR. On day 7, the hypothalamic and plasma concentration of the cytochemically detectable substance was significantly reduced in rats that received HC-3. The hypothalamic concentration was 225 +/- 95.6 x 10(8) G6PD U per hypothalamus (range 38.2-775) in SHR that received saline and 1.037 +/- 0.45 x 10(8) G6PD U (range 0.112-3.61) (p < 0.05) in SHR that received HC-3. The respective plasma concentrations were 284.9 +/- 26 U/ml (range 192-374) and 72.7 +/- 14.7 U/ml (range 24-119) (p < 0.05). The findings are consistent with the physicochemical evidence, which suggests that the cytochemically detectable substance is a choline derivative.(ABSTRACT TRUNCATED AT 250 WORDS)

Distribution of haemoglobin in patients presenting to their general practitioner, and its correlation with serum ferritin.

We have conducted a survey in the United Kingdom in order to evaluate the prevalence of anaemia and of iron deficiency in elderly male and female patients and in female patients of child-bearing age presenting to their general practitioner. Although haemoglobin values were approximately normally distributed, there was evidence of a bimodal distribution of serum ferritin values, particularly in elderly men. A correlation between serum ferritin and haemoglobin values was found to exist, both in the elderly and in younger women. The overall prevalence of anaemia in the study population was 14.3%, although it was higher for elderly men (20.1%) than either elderly women (13.7%) or women of child-bearing age (11.9%). Iron deficiency associated with anaemia was more common in elderly men (45.2% of those anaemic) than elderly women (28.6%) or women of child-bearing age (25.6%). This survey indicates that the prevalence of anaemia among certain groups of high risk patients presenting for consultation to their general practitioner is about 1 in 7, although the prevalence is as high as 1 in 5 in elderly men.

Effect of outlying standard points on curve fitting in radioimmunoassay.

Outlying points often appear in standard curves for radioimmunoassay. We have examined the effect of outlying standard points on the ability of various automated data-processing routines, and of manual operators, to position a radioimmunoassay standard curve correctly. Manual operators were found to be highly subjective in their handling of a standard curve containing outlying points. Automated methods without outlier rejection capability produced standard curves that were significantly erroneous. In contrast, a data-processing method with automated outlier rejection capability successfully identified outliers, but occasionally rejected valid points--and consequently misplaced the standard curve. Visual identification of outliers is unsatisfactory. Automated identification can be more satisfactory, but some patterns of outliers make it less so. We conclude that any automated data-processing method should contain an outlier rejection facility, but its results should be treated with caution.

Three different radioiodination methods for human spleen ferritin compared.

We compared three different methods for radioiodination of human spleen ferritin. Tracers prepared by direct oxidative iodination with use of Chloramine T or 1,3,4,6-tetrachloro-3 alpha, 6 alpha-diphenylglycoluril (Iodogen) were structurally altered by the labeling procedure, as was made apparent by gel filtration and electrophoresis on polyacrylamide gel. Tracers prepared by conjugation to radioiodinated N-succinimidyl-6-(4-hydroxyphenyl)propionate retained their structural integrity, as assessed by physicochemical methods. Such tracers bound more than 90% in antibody excess, yielded self-displacement curves parallel to unlabeled ferritin standards, and retained their immunoreactivity for nine weeks. By contrast, immunological activity and stability of tracers prepared by the oxidative methods were less satisfactory. Tracers prepared by using lodogen were unsuitable for use in the ferritin radioimmunoassay because of shallow standard-inhibition curves and poor binding in the absence of added standard. Thus, we found the conjugation procedure to be the most suitable of the three methods for preparation of spleen-ferritin tracers.

Thyroidal hormone metabolism in obesity during semi-starvation.

Six obese subjects were studied over a period of 12 weeks whilst on a 1260 kJ (300 kcal) formula diet. Weight loss was initially rapid, but later slowed markedly despite good patient compliance. The basal metabolic rate (BMR) fell in all patients during the study. Plasma triiodothyronine fell in all patients, whilst the plasma half-life of thyroxine increased. Plasma thyroxine, reverse triiodothyronine (reverse T3) and the serum prolactin and thyrotropin response to thyroliberin all showed no significant change.

Identification of an unusual gamma counter fault using Trigg's technique for trend detection.

A simultaneous deterioration in performance of several radioimmunoassays suggested that equipment was malfunctioning. Replicate counts from an automated gamma counter showed unacceptable variation during a 24-hour period; this variation was detected using Trigg's technique, a sensitive method for trend analysis, and was not identified by the usual laboratory testing procedures. A defective capacitor was found in the voltage stabilisation unit in the gamma counter, which probably made it responsive to small variations in the power supply to the laboratory. It is suggested that the analysis of replicate counts using Trigg's technique is a valuable test of gamma counter function which should become routine.

One year's experience with a regional hormone assay service.

To provide a service in England and Wales for specialised assays, clinical chemists envisaged a multi-tier system with area, regional, and supraregional laboratories. The Department of Clinical Biochemistry at Addenbrooke's Hospital was established as a regional centre for hormone assays and formal operation started in June 1975. The assays which seemed most suitable for regional development in East Anglia were those for investigating the pituitary-gonad and pituitary-thyroid axes. Most of these were introduced in the first year of operation. A specialised laboratory was not set up: instead, endocrine assays were integrated into a large service laboratory and little expenditure was needed for specialised facilities or staff. The work load of endocrine assays increased markedly during the first year of operation, but the main source of requests was local rather than regional. This lack of use by a region has implications for all three tiers of the specialised service. It suggests that effective centralisation of specialised assays is impracticable unless a dictatorial approach to the problem of rationalisation is made at regional and area level.

Interference in a radioimmunoassay for human thyrotropin.

Abnormally high plasma thyrotropin values were found by radioimmunoassay in some patients when an antiserum to porcine thyrotropin was used, normal results being obtained with an antiserum raised to human thyrotropin. These discrepancies were found in some subjects with no biochemical or clinical evidence of hypothyroidism and occasionally in sera from patients with unequivocal hyperthyroidism. We found a substance in serum that cross reacts with the anti-porcine antiserum, is stable on repeated freezing and thawing, and is independent of the 125I-labeled tracer preparation. It is unlikely that this substance is a separation-stage artefact related to immunoglobulins. Its apparent molecular weight (gel filtration) is 114 000, as compared with apparent molecular weights for standard thyrotropin and endogenous thyrotropin (as found in idiopathic hypothyroidism) of 34 700 and 38 000, respectively. We believe the substance is a normal serum constituent that is present in large quantities in a minority of subjects. Apparently unrelated to TSH, its exact chemical nature remains unidentified.

Observations on the automated calculation of radioimmunoassay results.

Radioimmunoassay standard curves derived by four different automated calculation methods are compared with those derived manually for five assays of clinical importance (thyroxine, triiodothyronine, thyrotrophin, alphafetoprotein, and human growth hormone). The three curve fitting methods (linear or cubic regression on log x versus logit y, cubic regression on log x versus y) produced considerable distortion of the manually derived curves, which in some cases could have impaired the accuracy of an estimate in a clinical sample and altered the clinical interpretation. Distortion patterns varied with the particular antigen assayed and with experimental conditions. In contrast, a simple linear interpolation method produced little distortion and gave results which were close to those derived manually in each assay examined.

Semi-automated radioimmunoassays for total serum thyroxine and triiodothyronine.

Single stage semi-automated radioimmunoassays for total serum thyroxine (T4) and triiodothyronine (T3) are described which employ an automatic pipetting station, automatic gamma counter, and a programmable calculator with paper tape reader and printing facility. Both assays require only a small volume of unextracted serum, and are specific and sensitive. Their sample capacity, precision, speed, and cost are comparable with the measurement of serum protein-bound iodine. Both assays therefore have significant advantages over previous methods for the assessment of thyroid function in the diagnostic laboratory. A Simple method of automating the calculation of results is described, which is applicable to any radioimmunoassay in which the standard curve is approximately linear on a plot of the free/bound fraction against the antigen concentration. In addition, a general method is reported which reveals the relative contributions of intrinsic, systematic, and random error to radioimmunoassay precision.

A critical evaluation of separation methods in radiommunoassay for total triiodothyronine and thyroxine in unextracted human serum.

Methods for separating free and antibody-bound hormone in radioimmunoassays for total triiodothyronine (T-3) and thyroxine (T-4) in unextracted human serum are evaluated. For T-3 assay, a simplified second antibody technique has significant advantages over other methods and gives a mean interassay coefficient of variation of 7.2% over a wide range of values. For T-4 assay, polyethylene glycol is the method of choice and has a mean interassay coefficent of variation of 4.7%. By adding the separating agents initially, the assays are readily semi-automated and may be completed within a working day.