Solomon Carter Fuller, M.D. (1872-1953): American pioneer in Alzheimer's disease research.

The appointment of Alois Alzheimer to Emil Kraepelin's clinic and laboratory at the Royal Psychiatric Hospital, University of Munich in 1903 offered new opportunities for clinical and pathological studies of the brain. At the opening of the facility in 1904, Alzheimer selected five foreign visiting students as his graduate research assistants, among whom was an American, Dr. Solomon Carter Fuller. A glimpse of Fuller's background as an African-American (born in Liberia) at the turn of the century, his continuing research after leaving Germany in 1906, and his critical view of the Alzheimer dementia entity are recounted. He was held in high esteem as a practicing neuropsychiatrist and teacher in the Boston area.

An overview of quality control practices in Ontario with particular reference to cholesterol analysis.

BACKGROUND: The Laboratory Proficiency Testing Program (LPTP) assesses the analytical performance of all licensed laboratories in Ontario. The LPTP Enzymes, Cardiac Markers, and Lipids Committee conducted a "Patterns of Practice" survey to assess the in-house quality control (QC) practices of laboratories in Ontario using cholesterol as the QC paradigm. DESIGN AND METHODS: The survey was questionnaire-based seeking information on statistical calculations, software rules, review process and data retention, and so on. Copies of the in-house cholesterol QC graphs were requested. A total of 120 of 210 laboratories were randomly chosen to receive the questionnaires during 1995 and 1996; 115 laboratories responded, although some did not answer all questions. RESULTS: The majority calculate means and standard deviations (SD) every month, using anywhere from 4 to >100 data points. 65% use a fixed mean and SD, while 17% use means calculated from the previous month. A few use a floating or cumulative mean. Some laboratories that do not use fixed means use a fixed SD. About 90% use some form of statistical quality control rules. The most common rules used to detect random error are 1(3s)/R4s while 2(2s)/4(1s)/10x are used for systematic errors. About 20% did not assay any QC at levels >5.5 mmol/L. CONCLUSIONS: Quality control data are reviewed daily (technologists), weekly and monthly (supervisors/directors). Most laboratories retain their QC records for up to 3 years on paper and magnetic media. On some QC graphs the mean and SD, QC product lot number, or reference to action logs are not apparent. Quality control practices in Ontario are, therefore, disappointing. Improvement is required in the use of clinically appropriate concentrations of QC material and documentation on QC graphs.

The use of biochemical markers in ischaemic heart disease: prefactory remarks.

There has been a lack of rigour in many test assessments. The seven well-accepted methodological standards, which are often ignored, are: (1) a suitable spectrum of the investigated population; (2) demarcation of significant clinical sub-groups; (3) avoidance of verification bias; (4) avoidance of review bias; (5) indices of test performance reported with their confidence intervals; (6) adequate handling of indeterminate results; (7) adequate test reproducibility. Additionally, rule-in and rule-out decision thresholds should be reported related to time after infarction. These decision thresholds are dependent on the particular methodology in use and confusion can, and does, result when comparing a value obtained with one analyzer with another. There is an urgent need for the standardization of analyte calibration. There are eight methodological standards for post-infarction prognosis studies. Less than 15% fulfilled these standards in a recent study of 766 such reports.

The use of biochemical markers in ischaemic heart disease: summary of the roundtable and extrapolations.

Acceptable biochemical markers of ischaemic heart disease are now considered to include myoglobin, CK-MB isoforms, CK-MB, and cardiac troponins T and I. AST (SGOT), total LD and LD isoenzymes, and total CK activity measurements are regarded as obsolete for this purpose. All acceptable biochemical markers must be available, if required, with a turnaround time of < 20 min. Such a service can either be provided by quantitative assays in a well-equipped laboratory or by qualitative point-of-care (bedside) devices (except for the CK-MB isoform assay) which can also be used in patients' homes and ambulances. There is, however, a pressing need for the careful side-by-side assessment of the relative merits of each of these biochemical markers to permit definitive conclusions about their future usage. A particular problem is the lack of primary standards for CK-MB and troponin I assays. The sensitivity of the initial ECG is about 50% for detecting myocardial damage; thus the use of biochemical markers may contribute to the early diagnosis and monitoring of thrombolytic therapy and these possible applications are examined. In addition, biochemical markers are presently the gold standard for the diagnosis of minor myocardial damage. There is now good evidence that biochemical markers, particularly the cardiac troponins, have a prognostic function in ischaemic heart disease although such findings pose unanswered clinical management questions. At the same time, it is recognized that there is often no need at all for the use of any biochemical marker when the clinical diagnosis is unequivocal, other than for prognosis, monitoring thrombolytic therapy, or diagnosing reinfarction.

Proficiency testing of creatine kinase and creatine kinase-2: the experience of the Ontario Laboratory Proficiency Testing Program.

The Ontario Laboratory Proficiency Testing Program has regularly monitored the analytical performance of total creatine kinase (CK) (approximately 230 participants) and CK isoenzyme-2 (CK-MB) (approximately 160 participants) throughout the entire province. Consistently, a wide dispersion of results has been observed not only between different analyzer systems but also among identical analyzers. Accordingly, the results of the last three proficiency surveys for these analytes were examined statistically to establish both the extent of these variations and the range of values reported for the male upper reference ranges. The results of many of the analyzer systems were significantly different from each other, as were many of the reference ranges. This unsatisfactory situation may only be remedied by the use of reference materials as shown by others. The consequences of these findings also effect the reliability of epidemiological surveys such as the WHO MONICA Project (Circulation 1994;90:583-612), which monitors deaths due to heart disease and includes cardiac enzyme results in its criteria.

Evaluation of the hepatic iron index as a diagnostic criterion for genetic hemochromatosis.

The hepatic iron index was originally described as a useful test to discriminate genetic hemochromatosis from alcoholic siderosis. To evaluate the hepatic iron index as a diagnostic criterion, it is essential to evaluate a cohort of hemochromatosis patients in whom the diagnosis has been established with great certainty. The presence of a sibling with identical human leukocyte antigen (HLA) and with iron overload was considered to be the gold standard for the diagnosis. Hepatic iron index was reviewed retrospectively in 55 homozygotes and in 189 patients who did not have hemochromatosis and were referred for hepatic iron analysis. Four of 55 homozygotes (7%) had a hepatic iron index of < or = 1.9. Hepatic iron concentration was increased in all 4 patients, ranging from 36 to 100 micromol/gm dry weight, (normal value <35.5 micromol/gm). Twelve of 189 (6%) patients without hemochromatosis had hepatic iron indexes > 1.9. The positive likelihood ratio for a hepatic iron index of 1.9 was 12.4. Area under the receiver operating characteristic curve was 0.94 (0.9 to 0.99, 95% confidence interval). The hepatic iron index remains a useful tool in the diagnosis of genetic hemochromatosis. However, it should not be an absolute criterion for the diagnosis and should be interpreted in combination with clinical assessment and genetic studies.

Assessment of clinical enzyme methodology: a probabilistic approach.

A number of techniques are available to assess the clinical value of enzyme methodologies including regression and discriminant analyses, expert systems, neural networks, and probabilistic. Each has its adherents but the probabilistic approach appears to be the most commonly used technique. This approach uses the fourfold contingency table that categorises subjects by both the presence or absence of the target disease-as defined by a gold standard test- and by a test result being above or below a chosen decision threshold. From this classification can be defined the test's sensitivity and specificity. By altering the decision threshold across the entire range of test values a series of sensitivity:specificity pairs can be tabulated. These may be plotted as 1-specificity (or false positive rate or fraction) versus sensitivity (or true positive rate or fraction) to create a receiver operator characteristic (ROC) curve. ROC curves can provide the accuracy of the test (the area under the curve with associated confidence intervals), the rule-in and rule-out decision thresholds, and the clinical power of the test (likelihood ratio). However, a review of three years' publications in a peer-reviewed journal indicated that much of this essential data is usually absent. It is argued that such publications should include the decision thresholds used, the area under the curve and its standard error, a statistical assessment of the difference between two or more ROC plots, the rule-in and rule-out decision thresholds (indicating if these change with time after the onset of disease), and the relevant likelihood ratios.

An overview and ranking of biochemical markers of cardiac disease. Strengths and limitations.

Comparing the performance of one biochemical marker of myocardial damage with another is bedeviled with many problems, including a lack of uniform calibration between instruments providing measurements of the same analyte and differing reference ranges and decision thresholds. Diagnostic groupings and various gold standards create difficulties in comparing analytic results. There is a lack of uniformity in test assessments and their use for diagnostic and prognostic purposes. Finally, there is an almost complete absence of data from economic and decision analyses of test usage. It is argued that a much more stringent and rigorous approach to these aspects is essential. The use of biochemical markers of cardiac damage is in a dynamic state, with new applications continually appearing and new markers being developed. It is therefore essential that a uniform and rigorous outlook be maintained to ensure both optimal and economic test utilization based on the previously outlined principles.

Discordance between results for serum troponin T and troponin I in renal disease.

Two patients were investigated for unexplained increases in troponin T. In the first patient, who had rhabdomyolysis and acute renal failure, troponin T reached a peak value of 13.50 micrograms/L (67.5-fold the upper reference limit). The second patient had chronic renal failure and the troponin T peak value was 2.85 micrograms/L (14.3-fold the upper reference limit). Clinical investigations indicated no evidence of myocardial damage. Serum or plasma specimens were analyzed for total creatine kinase (CK), CK-2 mass, CK-2 isoform ratio, myoglobin, troponin T, troponin I, and myosin light chains; all except troponin I were at above-normal concentrations. We also investigated six additional renal patients with above-normal troponin T; troponin I was slightly increased in only one of these six patients. Our findings demonstrate discordance between results for troponin T and troponin I in renal patients.

Biochemical markers of myocardial damage.

OBJECTIVE: To assess various biochemical markers of myocardial damage. METHODS AND RESULTS: Before routinely using any test as a biochemical marker of myocardial damage, the published evidence for its diagnostic utility must be critically assessed. Such assessment includes receiver operator curve (ROC) curve analyses, confidence interval estimates of claimed sensitivity and specificity values, and the effects of testing in serial and parallel modes. It is also necessary to establish the test's rule-in (high specificity) and rule-out (high sensitivity) decision thresholds that may vary with time after the onset of symptoms. The spectrum of ischemic heart disease includes acute (sudden death, non-Q- and Q-wave infarctions) and chronic (stable, unstable, and variant angina) conditions. Biochemical markers of myocardial damage are of most value in the diagnosis of acute ischemic heart disease, although increasingly some of these markers are being found to possess a prognostic value in chronic ischemic heart disease. The markers of enzymatic activity include aspartate aminotransferase, creatine kinase (together with isoenzymes and isoforms), and lactate dehydrogenase and isoenzymes. Creatine kinase isoenzyme-2 may also be measured immunologically, and this type of assay is in increasing use both because of its speed and because its blood levels rise earlier than the corresponding activities. The commercially available nonenzymatic markers are myoglobin and troponin T; troponin I is expected to become available in late 1995. While myoglobin is a nonspecific indicator of myocardial damage, its diagnostic value is due to its early appearance in blood. Troponin T is more cardiac specific, but the published data appears to suggest that the cardiac specificity of troponin I is superior. Troponin levels become abnormal at about the same time after the onset of symptoms as mass assays of creatine kinase isoenzyme-2; therefore, they are not useful as early markers of myocardial damage. CONCLUSION: The availability of these nonenzymatic markers of myocardial damage must force a reassessment of the continued use of the enzymatic markers. Are they necessary, and if so, which ones should be retained?

Combination (multiple) testing for myocardial infarction using myoglobin, creatine kinase-2 (mass), and troponin T.

We retrospectively determined the mass concentrations of myoglobin, creatine kinase-2 (CK-2), and troponin T in serial samples from 80 patients with confirmed myocardial infarction (MI) and 60 non-MI patients. Results from receiver operating characteristic curve analyses show that all three tests are comparable in their diagnostic utility within the first 12 h of infarction. Decision thresholds were selected at a constant rule-in specificity of 95% and rule-out sensitivities of 95% at, respectively, 3-6, 6-9, and 9-12 h intervals after the onset of symptoms. Test sensitivities and specificities were compared for each, used as: a single test; two-test parallel combination; three-test parallel combination; two-test series combination; and three-test series combination. Our results from combination testing indicate what for the early diagnosis of MI, a single serum myoglobin measurement has diagnostic utility at 3 h after the onset of symptoms, and myoglobin and CK-2 (mass) in combination later than 3 h following the onset of symptoms. Serum troponin T is diagnostically similar to CK-2 (mass), although it has superior cardiac-tissue specificity, but it is not as yet commercially available as a "stat" test. Therefore, we recommend using troponin T as a confirmatory test 9 h after the onset of MI. Based on our findings, we suggest a testing algorithm for the early biochemical diagnosis of MI.

Effect of cardiac filling pressures on the release of atrial natriuretic peptide during exercise in heart transplant recipients.

OBJECTIVE: To determine the influence of body posture and central hemodynamics on the plasma levels of immunoreactive atrial natriuretic peptide (irANP) during exercise in cardiac transplant patients. METHODS: Central hemodynamics, mixed expired gas and ventilatory measurements, and venous blood sampling (for irANP determination) were obtained in cardiac transplant patients at rest and during supine (n = 12) or upright (n = 12) graded cycle exercise. Cardiopulmonary and irANP responses to exercise were compared between the upright and supine postures. RESULTS: At rest (supine), irANP concentrations were similar in both groups (172 +/- 87 pg/mL supine and 182 +/- 72 pg/mL upright) and did not correlate with resting supine central hemodynamics. During exercise, central filling pressures increased in both groups but patients exercising in the supine position had a greater increase. Peak exercise right atrial pressure was 12 +/- 4 mmHg supine versus 7 +/- 5 mmHg upright (P < 0.005). Peak exercise pulmonary capillary wedge pressure was 22 +/- 6 mmHg supine versus 14 +/- 5 mmHg upright (P < 0.005). At peak exercise, irANP levels were greater in the supine than upright position (419 +/- 166 pg/mL supine versus 277 +/- 40 pg/mL upright, P < 0.05). The change in irANP from rest to peak exercise correlated (P < 0.05) with changes in pulmonary capillary wedge pressure (r = 0.67), systolic pulmonary artery pressure (r = 0.78) and right atrial pressure (r = 0.53). There was, however, no correlation between change in irANP and peak oxygen consumption, change in heart rate or change in mean arterial blood pressure. CONCLUSIONS: In cardiac transplant recipients, exercise is a stimulus for ANP secretion, and augmentation in plasma irANP levels during exercise is modulated by changes in central hemodynamics.

Is determination of creatine kinase-2 after electrophoretic separation accurate?

Since 1991, the Ontario Laboratory Proficiency Testing Program has assessed the analytical performance of creatine kinase (CK; EC 2.7.3.2) isoenzyme-2, using fresh human serum supplemented with purified human CK isoenzymes. In Ontario, the 142 laboratories licensed to analyze CK-2 use a variety of methods: electrophoresis-based, immunoinhibition, and mass assays. During a 1992 survey, duplicate CK-2 samples with different total CK activities showed poorer precision when analyzed after electrophoretic separation than by any other method. A 1993 survey designed to validate these observations conclusively showed that electrophoresis-based assays are subject to a bias proportional to the total CK activity. These survey results were confirmed by studies with selected patients' specimens. We therefore conclude that electrophoresis-based assays may not warrant their reputation as the gold standard for CK isoenzyme measurement.