Transactions of the House of Delegates,Los Angeles,April 30-May 3, 1961

The ideal test for visual screening is one which is easily performed by a technician with limited training, inexpensive and not time-consuming, easily understandable by all applicants, and one which will correspond generally with a more thorough examination by an ophthalmologist. The ideal screening technique should test accurately those functions needed for any particular occupation. The visual screeners now in great preponderance have certain advantages for ease and are generally acceptable for approximating the visual acuity. Visual screeners do not accurately test the astigmatic applicant, and they have not proven their value in testing depth perception and color vision. The use of the Harrington Flocks Screener is recommended for testing the visual field. The use of the Verhoeff Steropter for depth perception and the American Optical pseudoisochromatic plates for color testing is recommended when these tests are needed.The old Snellen test cards, or the projector chart for measuring distance vision, and the test cards for measuring near vision are often much more reliable than are the visual screeners.     

Acquired hemophilia in a patient with myeloma.

The generally accepted indications for stress testing in patients with coronary artery disease include confirming the diagnosis of angina, determining the limitation of activity caused by angina, assessing prognosis in patients with known coronary artery disease, assessing perioperative risk, and evaluating responses to therapy. In patients with a clinical scenario strongly suggestive of angina, testing is not necessary to diagnose coronary artery disease. The exercise treadmill-electrocardiogram test is the oldest and most extensively used stress test and can be reliably performed in patients who are clinically stable and who have an interpretable resting electrocardiogram. The addition of myocardial imaging agents such as thallium 201, technetium Tc 99m sestamibi, and technetium Tc 99m teboroxime increases the sensitivity and specificity for detecting coronary disease. Pharmacologic agents such as dipyridamole, adenosine, and dobutamine may be used in patients who cannot exercise adequately. Myocardial ischemia can also be evaluated by echocardiography, computed tomography, or magnetic resonance imaging, especially when additional information such as left ventricular and valvular function is desired. We review the indications for the noninvasive evaluation of coronary artery disease and the rationale for selecting a diagnostic test.     

Controlling the false discovery rate with constraints: the Newman-Keuls test revisited

The Newman-Keuls (NK) procedure for testing all pairwise comparisons among a set of treatment means, introduced by Newman (1939) and in a slightly different form by Keuls (1952) was proposed as a reasonable way to alleviate the inflation of error rates when a large number of means are compared. It was proposed before the concepts of different types of multiple error rates were introduced by Tukey (1952a, b; 1953). Although it was popular in the 1950s and 1960s, once control of the familywise error rate (FWER) was accepted generally as an appropriate criterion in multiple testing, and it was realized that the NK procedure does not control the FWER at the nominal level at which it is performed, the procedure gradually fell out of favor. Recently, a more liberal criterion, control of the false discovery rate (FDR), has been proposed as more appropriate in some situations than FWER control. This paper notes that the NK procedure and a nonparametric extension controls the FWER within any set of homogeneous treatments. It proves that the extended procedure controls the FDR when there are well-separated clusters of homogeneous means and between-cluster test statistics are independent, and extensive simulation provides strong evidence that the original procedure controls the FDR under the same conditions and some dependent conditions when the clusters are not well-separated. Thus, the test has two desirable error-controlling properties, providing a compromise between FDR control with no subgroup FWER control and global FWER control. Yekutieli (2002) developed an FDR-controlling procedure for testing all pairwise differences among means, without any FWER-controlling criteria when there is more than one cluster. The empirica example in Yekutieli's paper was used to compare the Benjamini-Hochberg (1995) method with apparent FDR control in this context, Yekutieli's proposed method with proven FDR control, the Newman-Keuls method that controls FWER within equal clusters with apparent FDR control, and several methods that control FWER globally. The Newman-Keuls is shown to be intermediate in number of rejections to the FWER-controlling methods and the FDR-controlling methods in this example, although it is not always more conservative than the other FDR-controlling methods.     

Incorporating genotypes of relatives into a test of linkage disequilibrium.

Genetic data from autosomal loci in diploids generally consist of genotype data for which no phase information is available, making it difficult to implement a test of linkage disequilibrium. In this paper, we describe a test of linkage disequilibrium based on an empirical null distribution of the likelihood of a sample. Information on the genotypes of related individuals is explicitly used to help reconstruct the gametic phase of the independent individuals. Simulation studies show that the present approach improves on estimates of linkage disequilibrium gathered from samples of completely independent individuals but only if some offspring are sampled together with their parents. The failure to incorporate some parents sharply decreases the sensitivity and accuracy of the test. Simulations also show that for multiallelic data (more than two alleles) our testing procedure is not as powerful as an exact test based on known haplotype frequencies, owing to the interaction between departure from Hardy-Weinberg equilibrium and linkage disequilibrium.     

Maternal serum alpha-fetoprotein screening programs and quality control for laboratories performing maternal serum and amniotic fluid alpha-fetoprotein assays: policy statement. American Society of Human Genetics.

Maternal serum alpha-fetoprotein (MSAFP) values are used primarily but not solely to predict the occurrence of open neural tube defects in the fetus; their use for prediction of Down''s syndrome is a new initiative under investigation. The test is a good one, as far as such a test can be, but it is imperfect, because false-negative and false-positive results both occur. In other words, it is not an infallible test. To use the test as effectively as is currently possible requires a program capable of supplying baseline values in sufficient number and the follow-up procedures necessary for interpretation of positive tests. In other words, it is not simply an office test. Because there is no effective treatment to relax the burden of neural tube defects in the large majority of patients, prevention of disease involves termination of pregnancy at present. In other words, use of the test is value laden and controversial for some sectors of society. Despite its imperfections, the need for an elaborate societal structure to apply it, and its value-laden context the test is considered by many as a necessary procedure to maintain normal standards of practice. Indeed, the American College of Obstetricians and Gynecologists issued a statement advising its fellows to be aware of the availability of MSAFP testing and to discuss such testing with patients. It is natural that confusion about protocol and anxiety about practice and its consequences are prevalent in this context. The American Society of Human Genetics (ASHG) offers here a statement about issues that affect MSAFP testing and the attendant pitfalls.     

Scaled marginal models for multiple continuous outcomes

In studies that involve multivariate outcomes it is often of interest to test for a common exposure effect. For example, our research is motivated by a study of neurocognitive performance in a cohort of HIV-infected women. The goal is to determine whether highly active antiretroviral therapy affects different aspects of neurocognitive functioning to the same degree and if so, to test for the treatment effect using a more powerful one-degree-of-freedom global test. Since multivariate continuous outcomes are likely to be measured on different scales, such a common exposure effect has not been well defined. We propose the use of a scaled marginal model for testing and estimating this global effect when the outcomes are all continuous. A key feature of the model is that the effect of exposure is represented by a common effect size and hence has a well-understood, practical interpretation. Estimating equations are proposed to estimate the regression coefficients and the outcome-specific scale parameters, where the correct specification of the within-subject correlation is not required. These estimating equations can be solved by repeatedly calling standard generalized estimating equations software such as SAS PROC GENMOD. To test whether the assumption of a common exposure effect is reasonable, we propose the use of an estimating-equation-based score-type test. We study the asymptotic efficiency loss of the proposed estimators, and show that they generally have high efficiency compared to the maximum likelihood estimators. The proposed method is applied to the HIV data.     

Screening for carriers of cystic fibrosis--a general practitioner's perspective.

The identification of the gene for cystic fibrosis has led to the possibility of population based screening for carriers of cystic fibrosis to identify couples at risk of having an affected child. Pilot studies have shown that screening is feasible and does not cause untoward anxiety, though the uptake of testing varies considerably with the setting and method of invitation. Screening offered at times when individuals (and health professionals) perceive it as directly relevant will probably gradually become established in the United Kingdom. This review examines the role of general practice in genetic carrier screening as exemplified by cystic fibrosis. General practice has a pivotal role from the beginning in providing individuals and couples with information, facilitating testing of patients'' relatives and of carriers identified by screening elsewhere (such as antenatal clinics), and offering testing in the context of reproduction. Screening for the cystic fibrosis gene will probably be followed by other genetic screening programmes.     

Modelling p-value distributions to improve theme-driven survival analysis of cancer transcriptome datasets

Background  

Theme-driven cancer survival studies address whether the expression signature of genes related to a biological process can predict patient survival time. Although this should ideally be achieved by testing two separate null hypotheses, current methods treat both hypotheses as one. The first test should assess whether a geneset, independent of its composition, is associated with prognosis (frequently done with a survival test). The second test then verifies whether the theme of the geneset is relevant (usually done with an empirical test that compares the geneset of interest with random genesets). Current methods do not test this second null hypothesis because it has been assumed that the distribution of p-values for random genesets (when tested against the first null hypothesis) is uniform. Here we demonstrate that such an assumption is generally incorrect and consequently, such methods may erroneously associate the biology of a particular geneset with cancer prognosis.     

Symposium on diarrhea. 3. Investigation of chronic diarrhea.

The practical approach to the investigation of diarrhea must be logical and based on anatomic considerations. The site of the underlying disorder may be determined by the clinical picture, and the logic of investigation will be influenced by the history. Important specific investigation in a case of colonic diarrhea include a careful rectal examination, stool inspection, sigmoidoscopy, rectal biopsy and barium enema study. Colonoscopy has been used, but its role has yet to be defined. In a case of small-bowel steatorrhea or diarrhea quantitative chemical estimation of the daily output of stool fat is useful, and to this investigation is added a small-bowel radiograph series and, if the radiographic findings are abnormal, small-bowel biopsy. Other investigations for small-bowel disease may include the breath test with carbon-14-labelled glycocholic acid, the lactose tolerance test, duodenal aspiration for giardiasis, analysis of serum immunoglobulins and, on occasion, isolation of vasoactive intestinal polypeptide hormone (which may aid the diagnosis of functioning tumours of the pancreas or small bowel). Investigations for pancreatic steatorrhea include abdominal radiography, performance of the secretin test and testing of the response to pancreatic replacement therapy. In some patients it may be useful to use endoscopic retrograde cholangiopancreatography to differentiate pancreatic carcinoma and chronic pancreatitis.     

Cost analysis in choosing group size when group testing for Potato virus Y in the presence of classification errors

In many areas of the world, Potato virus Y (PVY) is one of the most economically important disease problems in seed potatoes. In Taiwan, generation 2 (G2) class certified seed potatoes are required by law to be free of detectable levels of PVY. To meet this standard, it is necessary to perform accurate tests at a reasonable cost. We used a two‐stage testing design involving group testing which was performed in Taiwan's Seed Improvement and Propagation Station to identify plants infected with PVY. At the first stage of this two‐stage testing design, plants are tested in groups. The second stage involves no retesting for negative test groups and exhaustive testing of all constituent individual samples from positive test groups. In order to minimise costs while meeting government standards, it is imperative to estimate optimal group size. However, because of limited test accuracy, classification errors for diagnostic tests are inevitable; to get a more accurate estimate, it is necessary to adjust for these errors. Therefore, this paper describes an analysis of diagnostic test data in which specimens are grouped for batched testing to offset costs. The optimal batch size is determined by various cost parameters as well as test sensitivity, specificity and disease prevalence. Here, the Bayesian method is employed to deal with uncertainty in these parameters. Moreover, we developed a computer program to determine optimal group size for PVY tests such that the expected cost is minimised even when using imperfect diagnostic tests of pooled samples. Results from this research show that, compared with error free testing, when the presence of diagnostic testing errors is taken into account, the optimal group size becomes smaller. Higher diagnostic testing costs, lower costs of false negatives or smaller prevalence can all lead to a larger optimal group size. Regarding the effects of sensitivity and specificity, optimal group size increases as sensitivity increases; however, specificity has little effect on determining optimal group size. From our simulated study, it is apparent that the Bayesian method can truly update the prior information to more closely approximate the intrinsic characteristics of the parameters of interest. We believe that the results of this study will be useful in the implementation of seed potato certification programmes, particularly those which require zero tolerance for quarantine diseases in certified tubers.     

Diagnostic utility of oncogenes and their products in human cancer.

The first clear cut association of an oncogene with a specific cancer is the c-abl translocation in chronic myelogenous leukemia and acute lymphocytic leukemia; it has been observed in 90% of CML cases examined. This is the major contributing factor to its being the target of the first oncogene-based FDA-approved diagnostic test. Although the role of the abl translocation in the tumorigenic process is not yet understood, it is clear that somehow it must be causally related to the disease, and thus is an ideal target for a diagnostic test. The association of this oncogene with a specific cancer is the model on which all others may be based in the future. Second generation tests could easily include PCR on mRNA, and/or in situ hybridization, both of which could be performed using blood samples. Both methods would provide a faster means of testing a large number of cells, however, the methodologies must be improved through automation and computer-aided image analysis, respectively, in order to become useful routine tests. Both neu and epidermal growth factor receptor (EGFR) appear to have a close correlation between overexpression of the gene product and outcome of disease in breast cancer; valuable information for prognosis of the disease. And again, although the actual mechanism of action of these molecules and how this relates to the tumorigenic process is not yet known, it is believed from the very nature of the molecules that they must in some way contribute to the progression of the disease. In both cases, the protein products are overexpressed in tissue, and in the case of Neu, it appears as through at least some of the patients have a Neu-related protein in their serum. These molecules present relatively easy targets for the development of diagnostic/prognostic assays, as antibodies are easily made and can be incorporated into a variety of assay formats. Current assays available, an ELISA for Neu and a radio-ligand binding assay for EGFR, are highly sensitive, reproducible and relatively easy to perform. Only the ELISA is commercially available, however, and hence allows for easy comparison between laboratories. An abvious step towards the routine measurement of EGFR then is the development of a comparable commercially available test. An improvement for both types of assay would be the incorporation of an internal control to gauge the cellular component of the tissue samples that are tested. The outcome of the applications of myc and ras to cancer diagnostics is not so easily predictable, with a couple of exceptions.(ABSTRACT TRUNCATED AT 400 WORDS)     

Considerations in the U.S. Environmental Protection Agency's testing approach for mutagenicity.

OPP: This paper provides the rationale and support for the decisions the OPP will make in requiring and reviewing mutagenicity information. The regulatory requirement for mutagenicity testing to support a pesticide registration is found in the 40 CFR Part 158. The guidance as to the specific mutagenicity testing to be performed is found in the OPP's Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Animals (referred to as the Subdivision F guideline). A revised Subdivision F guideline has been presented that becomes the current guidance for submitters of mutagenicity data to the OPP. The decision to revise the guideline was the result of close examination of the version published in 1982 and the desire to update the guidance based on developments since then and current state-of-the-science. After undergoing Agency and public scrutiny, the revised guideline is to be published in 1991. The revised guideline consists of an initial battery of tests (the Salmonella assay, an in vitro mammalian gene mutation assay and an in vivo cytogenetics assay which may be either a bone marrow assay for chromosomal aberrations or for micronuclei formation) that should provide an adequate initial assessment of the potential mutagenicity of a chemical. Follow-up testing to clarify results from the initial testing may be necessary. After this information as well as all other relevant information is obtained, a weight-of-evidence decision will be made about the possible mutagenicity concern a chemical may present. Testing to pursue qualitative and/or quantitative evidence for assessing heritable risk in relation to human beings will then be considered if a mutagenicity concern exists. This testing may range from tests for evidence of gonadal exposure to dominant lethal testing to quantitative tests such as the specific locus and heritable translocation assays. The mutagenicity assessment will be performed in accordance with the Agency's Mutagenicity Risk Assessment Guidelines. The mutagenicity data would also be used in the weight-of-evidence consideration for the potential carcinogenicity of a chemical in accordance with the Agency's Carcinogen Risk Assessment Guidelines. In instances where there are triggers for carcinogenicity testing, mutagenicity data may be used as one of the triggers after a consideration of available information. It is felt that the revised Subdivision F guideline will provide appropriate, and more specific, guidance concerning the OPP approach to mutagenicity testing for the registration of a pesticide. It also provides a clearer understanding of how the OPP will proceed with its evaluation and decision making concerning the potential heritable effects of a test chemical.(ABSTRACT TRUNCATED AT 400 WORDS)     

A suspension method to determine reuse life of chemical disinfectants during clinical use.

In-use testing of disinfectants is necessary to ensure efficacy over time. The current official procedure for testing disinfectants, the Association of Official Analytical Chemists (AOAC) use-dilution method, cannot be adapted to repeated sampling techniques of use-life testing. It is therefore necessary to use an alternative method when evaluating the activity of a disinfectant under actual use. The Clinical Research Associates (CRA) suspension method was developed to fill this need. It consists of adding 0.5 ml of a standard culture to 5.0 ml of test disinfectant and sampling the mixture after 10 min for surviving bacteria. When this test was compared with the AOAC use-dilution method under a simulated use situation, the two methods were generally equivalent in identifying disinfectant inactivation. In addition, the CRA method was less time consuming, easier to perform, and less variable than the AOAC method. Use of the CRA method in a clinical study demonstrated the need for reuse claims to be based on clinical use studies rather than on laboratory testing only.     

The importance of the prediction model in the validation of alternative tests

An overview is presented of the validation process adopted by the European Centre for the Validation of Alternative Methods, with particular emphasis on the central role of the prediction model (PM). The development of an adequate PM is considered to be just as important as the development of an adequate test system, since the validity of an alternative test can only be established when both components (the test system and the PM) have successfully undergone validation. It is argued, however, that alternative tests and their associated PMs do not necessarily need to undergo validation at the same time, and that retrospective validation may be appropriate when a test system is found to be reliable, but the case for its relevance remains to be demonstrated. For an alternative test to be considered "scientifically valid", it is necessary for three conditions to be fulfilled, referred to here as the criteria for scientific relevance, predictive relevance, and reliability. A minimal set of criteria for the acceptance of any PM is defined, but it should be noted that required levels of predictive ability need to be established on a case-by-case basis, taking into account the inherent variability of the alternative and in vivo test data. Finally, in view of the growing shift in emphasis from the use of stand-alone alternative tests to alternative testing strategies, the importance of making the PM an integral part of the testing strategy is discussed.     

Pooling data for stability studies: testing the equality of batch degradation slopes.

Pharmaceutical products are routinely monitored for their stability over time. Stability studies generally consist of a random sample of dosage units (e.g., tablets, capsules, vials) from a batch or several batches placed in a storage room and periodically assayed for their drug content. The degradation of the drug product is modeled, and according to the Guideline for Submitting Documentation for Stability Studies of Human Drugs and Biologics (Food and Drug Administration, 1987), the shelf-life is calculated as the time point at which the lower 95% confidence limit about the fitted regression line crosses the lowest acceptable limit for drug content (frequently 90% of the labeled amount). When multiple batches are manufactured, preliminary testing for any batch differences (both slope and intercept) should precede pooling stability data from all batches in the analysis. The Guideline recommends a level of significance of .25 for such preliminary testing based on the work described by Bancroft (1964, Biometrics 20, 427-442). Using such a large significance level helps ensure that the power of the test for the batch differences is sufficiently high. This paper presents an approach whereby the power of the test is fixed and the significance level of the test needed to obtain this power is calculated from the data. If the observed significance level does not achieve the calculated significance level, then the data can be pooled. Examples will illustrate the relative performance of the FDA guideline and the proposed procedure.     

DNA-based genetic testing is rising steeply in a national health care system with open access to services: a survey of genetic test use in Germany, 1996-2002

The extent to which the fast-growing body of genetic knowledge is transferred into everyday clinical practice has nowhere been assessed in a systematic way. Available quantitative analyses of DNA-based genetic test provision and uptake rates are all concerned with specific test programs. The German health-care system is ideally suited for a more general approach, because it is highly flexible regarding access to services, thus permitting quick adjustments to sudden changes in particular subfields of medicine such as genetic testing. We have measured the amount of genetic service provision in Germany between 1996 and 2002 by making use of the central database of the German national health-care system and by inquiring with private health insurance. We can document a three-fold increase of DNA-based testing in the time period 1996-2002, whereas cytogenetic analyses and genetic counseling have remained constant. The growing body of genetic knowledge does indeed seem to be transferred into medical practice at an increasing rate, and the uptake rates are largely in proportion to test offers. DNA-based testing appears to be focussed on disease-associated germ-line alterations.     

Characteristics of false-negative smears tested in the normal screening situation.

It is common practice to rescreen false-negative (FN) smears. However, it is inevitable that this is done with some foreknowledge; at least it is known that the test smears contain one or more special cases. Therefore, we decided to test smears in the normal screening situation, when cytotechnologists are completely unaware of being tested. This experiment was done with five FNs and five true-positive (TP) smears. In a third experiment the FNs were tested with the cytotechnologists aware of their presence. Finally, 10 qualities of FNs and TPs were analyzed. In the normal screening situation, only in 1 of 25 tests was the FN recognized as malignant, while all the TPs were detected at the first testing. However, when the cytotechnologists were aware of being tested, the FN was detected in seven of eight tests. The FNs differed from the TPs in 5 of the 10 analyzed characteristics. FNs contained few (if any) large neoplastic epithelial fragments. Detached malignant cells were nearly lacking. The cancer cells had small nuclei that presented little anisokaryosis. The FNs possessed generally hypochromatic nuclei. These features explain why the malignant cells were almost never identified in the normal screening situation. We conclude that FNs and TPs differ and that it seems virtually impossible to avoid all false-negative diagnoses.     

Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens III. Appropriate follow-up testing in vivo

There has been much discussion in recent years regarding the most appropriate follow-up testing in vivo when positive results are obtained in vitro but the in vivo micronucleus (MN) test (traditionally the most widely-used test) is negative. Not all rodent carcinogens give positive results in the micronucleus test, and so it has been common practice to include a second in vivo assay such as the unscheduled DNA synthesis (UDS) test. This has proved useful but is usually limited to analysis of rodent (usually rat) liver. With the increased evaluation and use of other in vivo assays, e.g. for transgenic mutations (TG) and DNA damage (Comet assay) it was important to investigate their usefulness. We therefore examined the published in vivo UDS, TG and Comet-assay results for 67 carcinogens that were negative or equivocal in the micronucleus test. Between 30 and 41 chemicals were evaluated in each of the three in vivo tests, with some overlap. In general, the UDS test was disappointing and gave positive results with <20% of these carcinogens, some of which induced tumours in rat liver and produced DNA adducts in vivo. The TG assay gave positive responses with >50% of the carcinogens, but the Comet assay detected almost 90% of the micronucleus-negative or equivocal carcinogens. This pattern of results was virtually unchanged when the in vitro profile (gene mutagen or clastogen) was taken into account. High sensitivity (ability to detect carcinogens as positive) is only really useful when the specificity (ability to give negative results with non-carcinogens) is also high. Based on small numbers of publications with non-carcinogens, the TG and Comet assays gave negative results with non-carcinogens on 69 and 78% of occasions, respectively. Although further evaluation of the Comet and TG assays, particularly with non-carcinogens, is needed, these data suggest that they both should play a more prominent role in regulatory testing strategies than the UDS test.     

Strategy for genotoxicity testing: hazard identification and risk assessment in relation to in vitro testing

This report summarizes the proceedings of the September 9-10, 2005 meeting of the Expert Working Group on Hazard Identification and Risk Assessment in Relation to In Vitro Testing, part of an initiative on genetic toxicology. The objective of the Working Group was to develop recommendations for interpretation of results from tests commonly included in regulatory genetic toxicology test batteries, and to propose an appropriate strategy for follow-up testing when positive in vitro results were obtained in these assays. The Group noted the high frequency of positive in vitro findings in the genotoxicity test batteries with agents found not to be carcinogenic and thought not to pose a carcinogenic health hazard to humans. The Group agreed that a set of consensus principles for appropriate interpretation and follow-up testing when initial in vitro tests are positive was needed. Current differences in emphasis and policy among different regulatory agencies were recognized as a basis of this need. Using a consensus process among a balanced group of recognized international authorities from industry, government, and academia, it was agreed that a strategy based on these principles should include guidance on: (1) interpretation of initial results in the "core" test battery; (2) criteria for determining when follow-up testing is needed; (3) criteria for selecting appropriate follow-up tests; (4) definition of when the evidence is sufficient to define the mode of action and the relevance to human exposure; and (5) definition of approaches to evaluate the degree of health risk under conditions of exposure of the species of concern (generally the human). A framework for addressing these issues was discussed, and a general "decision tree" was developed that included criteria for assessing the need for further testing, selecting appropriate follow-up tests, and determining a sufficient weight of evidence to attribute a level of risk and stop testing. The discussion included case studies based on actual test results that illustrated common situations encountered, and consensus opinions were developed based on group analysis of these cases. The Working Group defined circumstances in which the pattern and magnitude of positive results was such that there was very low or no concern (e.g., non-reproducible or marginal responses), and no further testing would be needed. This included a discussion of the importance of the use of historical control data. The criteria for determining when follow-up testing is needed included factors, such as evidence of reproducibility, level of cytotoxicity at which an increased DNA damage or mutation frequency is observed, relationship of results to the historical control range of values, and total weight of evidence across assays. When the initial battery is negative, further testing might be required based on information from the published literature, structure activity considerations, or the potential for significant human metabolites not generated in the test systems. Additional testing might also be needed retrospectively when increase in tumors or evidence of pre-neoplastic change is seen. When follow-up testing is needed, it should be based on knowledge about the mode of action, based on reports in the literature or learned from the nature of the responses observed in the initial tests. The initial findings, and available information about the biochemical and pharmacological nature of the agent, are generally sufficient to conclude that the responses observed are consistent with certain molecular mechanisms and inconsistent with others. Follow-up tests should be sensitive to the types of genetic damage known to be capable of inducing the response observed initially. It was recognized that genotoxic events might arise from processes other than direct reactivity with DNA, that these mechanisms may have a non-linear, or threshold, dose-response relationship, and that in such cases it may be possible to determine an exposure level below which there is negligible concern about an effect due to human exposures. When a test result is clearly positive, consideration of relevance to human health includes whether other assays for the same endpoint support the results observed, whether the mode or mechanism of action is relevant to the human, and - most importantly - whether the effect observed is likely to occur in vivo at concentrations expected as a result of human exposure. Although general principles were agreed upon, time did not permit the development of recommendations for the selection of specific tests beyond those commonly employed in initial test batteries.     

The role of physicians as medical review officers in workplace drug testing programs. In pursuit of the last nanogram.

In discussing the role of physicians in workplace drug testing programs, I focus on the recent Department of Transportation regulations that require drug testing in such regulated industries as interstate trucking, air transportation, mass transit, and the railroads. These regulations require that applicable drug testing programs employ physicians as medical review officers to evaluate positive tests that have been screened and confirmed by different techniques to determine if there is a legal medical explanation for the result. The drug testing program tests for the presence of amphetamine, cocaine, tetrahydrocannabinol, opiates, and phencyclidine. If an employee testing positive has an acceptable medical explanation, the result is to be reported as negative. Little practical advice exists for medical review officers, and they must be aware of key elements of the regulations and potential trouble spots.