A multicenter evaluation of sweat chloride concentration and variation in infants with cystic fibrosis.

Fifty-nineCF infants' sweat chloride concentrations were analyzed to answer the questions: What is the biological and analytical variation in sweat chloride concentrations collected from the 32 infants homozygous for the F508 deletion? Do sweat chloride concentrations change in the first year of life beyond the variance previously established for adults with similar CFTR mutations? The biological and analytical variation of the infants' sweat chloride concentration was similar to that seen in adult CF patients. While there was a statistically significant difference between sweat chloride concentration in early (89.8 mmol/L) and late (95.0 mmol/L) infancy, this change is not likely clinically significant. This suggests that sweat chloride concentrations in CF patients do not change in a meaningful way during the first year of life. Determining variability in infants with CF is the necessary first step for future design of clinical trials of CFTR modulators in younger patients.

Analytical and biological variation in repeated sweat chloride concentrations in clinical trials for CFTR modulator therapy.

BACKGROUND: Using sweat chloride as a biomarker for CFTR modifying drugs requires knowledge of analytical and biological variation. METHODS: 979 sweat chloride concentrations from 128 subjects enrolled in the placebo arm of 2 multicenter, investigational drug trials were analyzed to determine coefficients of variation (CV) as well as reference change value (RCV) and index of individuality (II). RESULTS: For these populations, calculated values for the two studies were: analytical variation (3.9, 4.1%); within-subject variation (4.4, 6.0%); between-subject variation (8.9, 7.0%); RCV (13.7, 17.0%) and II (0.7, 1.0). Sweat chloride variation was not affected by sex, collection site or sample weight; but was slightly affected by age in one of the two studies. CONCLUSION: Through determination of analytical as well as between- and within-subject variation, and with a larger sample size, our data allows improved estimates of the RCV and II, and can contribute to future trials of CFTR modulators and inform the design and interpretation of n of 1 trials in both research and clinical settings.

Assessment of sweat-testing practices for the diagnosis of cystic fibrosis.

OBJECTIVE: To describe the results of the College of American Pathologists survey questions assessing the current practice of sweat testing in North America and to identify areas in which improvement is needed. DATA SOURCE: Results of the supplemental questions to the SW-B 2000 survey. STUDY SELECTION: Supplemental questions were designed to assess variation in sweat collection, analysis, and interpretation. DATA EXTRACTION: Extractions of the data were made based on the relevance of the data to the objectives of the review. DATA SYNTHESIS: The majority of laboratories surveyed performed sweat testing according to the procedures described in the National Committee for Clinical Laboratory Standards' document. The study revealed that a number of laboratories have adopted poor practice standards and are potentially compromising patient care. Areas of concern include the number of laboratories performing few sweat tests per year, the persistence of unreliable methodology, misunderstanding of collection parameters, lack of patient education, and erroneous result reporting. CONCLUSIONS: The study identified areas of concern toward which educational efforts can be directed. Such efforts include the development of a College of American Pathologists accreditation checklist for sweat testing and targeted responses in the sweat analysis participant summary report.

A modified technique for measurement of nasal transepithelial potential difference in infants.

OBJECTIVE: To establish a method for measuring nasal transepithelial potential difference (PD) in infants. STUDY DESIGN: A modified infant method (smaller catheter size, reduced flow rates, and shorter protocol time) was compared with an established adult nasal PD method in 10 adult volunteers (4 with cystic fibrosis [CF]). Nasal PD was measured in 13 infants with a possible diagnosis of CF. RESULTS: Recordings were similar for the established and the modified methods in adult volunteers. An amiloride concentration of 10(-4) mol/L was necessary for full inhibition of amiloride-sensitive sodium ion (Na(+)) transport. Of the 13 infants, 2 had PD values suggestive of CF (mean baseline PD, -50.1 mV and -31.4 mV; maximum baseline PD, -61 mV and -49 mV; change in PD after perfusion with zero chloride solution with isoprenaline and amiloride [DeltazeroCl(-)/Iso], -1 mV and +3.5 mV), and 11 had normal values (mean +/- SEM baseline PD, -13.2 +/- 1.0 mV; maximum baseline PD, -21.4 +/- 2.0; DeltazeroCl(-)/Iso, -15.3 +/- 1.9 mV). These results correlated with subsequent sweat test data, mutation analysis, and clinical outcome. CONCLUSION: Nasal PD measured with this modified method is comparable to that measured with an established adult method. The measurements were well tolerated in 13 infants and discriminated bioelectric profiles characteristic of normal and CF respiratory epithelium. This study supports the use of this modified nasal PD technique as a diagnostic test for CF in newborn infants.

Hereditary hemochromatosis: a case study and review.

Hereditary hemochromatosis (HH) is a disorder of iron regulation that leads to excessive iron absorption. Over time, the resultant iron overload and deposition in tissue leads to various chronic diseases and premature death. Even though it is the most common genetic disorder among Caucasians in the U.S., hereditary hemochromatosis often goes undetected or unrecognized by healthcare providers. Laboratory tests provide effective, inexpensive means of screening for and confirming hereditary hemochromatosis. The clinical laboratory also plays a key role in hereditary hemochromatosis treatment, reduction of iron stores through therapeutic phlebotomy.

Sweat analysis proficiency testing for cystic fibrosis.

The purpose of this report is to describe the College of American Pathologists sweat testing (SW) proficiency testing program for cystic fibrosis, to evaluate its impact on test performance, and to describe the current practice of sweat testing in North America. The study analyzed participant summary reports of the SW survey from 1994-1998 (SW 94-98) and Proficiency Testing Exception Summary reports from 1996-1998. The data collected from SW 94-98 allowed for the assessment of trends and/or changes in sweat testing practices. The data collected from SW-A 1998 provided a profile of current practices in sweat testing. While the overall performance on the SW survey is encouraging, the program has identified areas of concern. The number of poorly performing laboratories are few in number, yet if the reported results had been patient specimens, the clinical implications would have been significant. The SW survey is meeting its goal of providing feedback to institutions on their performance of sweat analysis and providing educational materials on the total testing process in an effort to improve the quality of sweat testing. Significant changes in practice have occurred in many institutions performing sweat tests, and a greater awareness of analyte identification has resulted.

Coronary heart disease in women and the role of the laboratory.

Coronary heart disease (CHD), the single greatest cause of death in women, is often unrecognized by health care providers and individuals suffering from the disease. CHD is a process in which atherosclerotic lesions composed of lipoprotein particles, macrophages, leukocytes, and smooth muscle cells narrow the lumen of coronary arteries. Two clinical conditions may develop, acute myocardial infarction (AMI) and unstable angina. Signs and symptoms of CHD in women may differ from those of men, leading to delays in treatment and diagnosis. Several well-recognized risk factors for CHD have been identified, including aging, hypertension, hyperlipidemia, diabetes, smoking, obesity, and sedentary lifestyle. The role of the laboratory in CHD involves diagnosing and monitoring persons at risk for developing CHD, diagnosing AMI, monitoring effectiveness of perfusion post AMI, and patient risk stratification.

Sweat testing for the diagnosis of cystic fibrosis: practical considerations.

Most pediatricians eventually encounter a patient with a clinical presentation that warrants the consideration of a sweat test to rule out of confirm the diagnosis of cystic fibrosis. This article discusses, in a series of questions and answers, the currently available sweat testing methods and describes the various methods' reliability, limitations, and frequency of use. In addition, sweat testing utilization and the interpretation and evaluation of test results are discussed so that the clinician can critically analyze the laboratory data.

Legal aspects associated with dismissal from clinical laboratory education programs.

OBJECTIVE: To review academic dismissals, students' rights in dismissal cases, and several key cases involving academic and disciplinary dismissals. DATA SOURCES: Recent academic literature and legal precedents. STUDY SELECTION: Not applicable. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: Students involved in dismissals are protected under the principles of constitutional law and/or contract law, depending on whether the institution is public or private. The basis for dismissal from educational programs is either academic or disciplinary in nature. In academic dismissals, a student has failed to meet either the cognitive or the noncognitive academic standards of the program. In disciplinary dismissals, a student has violated the institutional rules governing conduct. Policies that affect progress in the program and the dismissal process should be published and distributed to students, as well as reviewed for consistency with institutional policies. CONCLUSION: The amount of documentation needed in the defense of a dismissal decision has not been specified, but, in general, more is better. Procedures are suggested as a guide to dismissals in clinical laboratory programs.

Legal issues relevant to clinical laboratory education program admissions.

OBJECTIVE: To address the basic legal requirements for admissions, admissions standards, student and applicant records, and discrimination in admissions for clinical laboratory science (CLS) and clinical laboratory technician (CLT) educational programs. DATA SOURCES: Recent academic literature and legal precedents. STUDY SELECTION: Not applicable. DATA EXTRACTION: Not applicable. DATA SYNTHESIS: CLS and CLT educational programs typically practice selective admissions. Program directors and faculty need to be aware of the issues relating to student selection that may have legal implications. Admissions practices should be guided by three basic legal requirements: that the selection process not be arbitrary or capricious, that the program adhere to its published admissions standards and honor admissions decisions, and that the program not have admissions policies that discriminate on the basis of race, gender, age, disability, or citizenship. Specific guidelines are offered for applying these legal requirements to the admissions practices typically used by CLS and CLT programs, including published admission policies and standards, application forms, interviews, rating of noncognitive attributes, and communication with applicants. CONCLUSION: Admissions practices in CLS and CLT programs need to be guided by the three basic legal requirements.

Current status of sweat testing in North America. Results of the College of American Pathologists needs assessment survey.

The College of American Pathologists surveyed 5096 laboratories for information concerning collection and analytic methodologies used in the performance of the sweat test. The test measures the concentration of electrolytes in sweat and is an essential criterion for the diagnosis of cystic fibrosis. An 83% response rate was achieved on the needs assessment survey, representing the first large-scale, national study of sweat testing practices. Nineteen percent of the respondents perform sweat testing in their laboratory, and the majority of the respondents analyze the sweat for chloride concentration. Fifty-nine percent of the laboratories performing sweat testing indicated an interest in participating in proficiency testing for sweat analysis. The information gathered from the needs assessment survey will be used to develop a comprehensive proficiency testing program to provide feedback and education to laboratories performing this critical diagnostic test.

Assessing quality assurance for sweat chloride testing.

Variations in sweat chloride tests were analyzed. A total of 1,806 sweat test results were analyzed for intra-assay and inter-assay variation in sweat chloride concentration and sweat weight. The mean and standard deviation of sweat chloride determinations for the negative population was 11.63 mmol/L (7.20 s.d.); for the borderline population was 50.01 mmol/L (6.27 s.d.); and for the positive population was 96.75 mmol/L (s.d. = 13.81). The percent of sweat tests that were negative was 86.77, borderline, 3.82, and positive, 9.41. The variation, represented as the standard deviation, between bilateral sweat chloride values on the same patient for negative results is 10.23 and for positive results is 14.60. The average variation within a patient with regard to sweat weight is 19%. Clinical laboratory scientists can use this information in assessing their own quality assurance procedures and patient results.

Incidence and implications of false-negative sweat test reports in patients with cystic fibrosis.

It is well known that false-positive sweat tests occur commonly, but since a positive test should always be repeated, such an error is likely to be discovered. False-negative results, however, are more difficult to detect and are generally assumed to be much less frequent than false-positive results. Diagnostic delay caused by false-negative reports may lead to substantial morbidity. Review of the medical records of 147 unselected patients with cystic fibrosis followed in our center revealed that 17 (12%) initially had one or more sweat tests that were falsely negative (or were so reported or interpreted). In seven patients, there was diagnostic delay with adverse clinical consequences. Many factors may contribute to the incidence of false-negative sweat tests, and negative results must not be accepted as definitively excluding cystic fibrosis if the clinical syndrome is otherwise suggestive.

Clinical applications of DNA probes in the diagnosis of genetic diseases.

Currently, advances in molecular technology involving recombinant DNA have led to dramatic breakthroughs in genetic diseases, cancer research, and identification of foreign DNA. Of particular interest is the impact these tools have made and will make on the clinical laboratory. We describe the techniques and their effects on clinical testing in the chemistry laboratory by using selected examples of available applications. Specific examples include carrier detections and prenatal diagnosis in cystic fibrosis and hemophilia, and sickle cell anemia.