False-negatives

In general the rate of false negatives are by definition difficult to ascertain. There are two general approaches to get a handle on false negatives. The first approach is based on what is known about the aqueous solubility of screening compounds since truly active compounds out of solution are the most common cause of false negatives. One can infer that perhaps 15% of true positives will be missed in an HTS. This inference comes from an analysis of the concordance or lack of concordance between nominal concentrations in DMSO stocks and nominal 

A second approach to handling false negatives relies on a computational analysis of actives in the primary HTS. Were there analogs or similar compounds to actives that appeared inactive in the original HTS These inactives are retested perhaps in a more careful screen and some of the original inactives will now be found to be active. Most commonly these were truly active compounds that appeared inactive in the original screen because they were not in solution under the initial HTS assay conditions. 

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Sensitive to toxins, in this case means that the assay presents no false negative results. Primary hepatocytes can elucidate hepatotoxins, and mouse neuroblastoma cells can elucidate sodium channel-blocking neurotoxins therefore these assays can be used to screen for the appropriate toxins. 

A major consideration in screening is the detection capability of the screen for both false negatives (lack of detection of an active drug) and propensity to find false positives (detection of a response to the compound not due to therapeutic activity of interest). Ostensibly, false positives might not be considered a serious problem in that secondary testing will detect these and they do not normally interfere with the drug discovery process. 

F statistic, 239, 241 False negatives, 152—153 False positives, 152—153 Fenoximone, 188 First-order kinetics, 167 Fluorescence resonance energy transfer, 182... 

False negative muscle contraction tests are very rare. To date, a negative muscle contraction test rules out MH. A false negative test can be explained by the presence of two types of muscle fibers in a MH susceptible patient the response being dependent on the proportion of the two types of muscle fibers. The K-type designation is used to describe a patient who has a positive joint halothane-caffeine contracture, but a negative separate halothane or caffeine contracture. Whether K-type individuals are MH-susceptible or not is a controversial issue. 

Over the years an abundance of outlier tests have been proposed that have some theoretical rationale at their roots. ° Such tests have to be carefully adjusted to the problem at hand because otherwise one would either not detect true outliers (false negatives) in every case, or then throw out up to 50% of the good measurements as well (false positivesj. o Robust methods have been put forward to overcome this. Three tests will be described ... 

Decision taken. null hypothsis Ho our product is the same have R D come up with new ideas false negative loss of a good marketing argument hopefully the customer will appreciate the difference in quality Risk is hard to estimate... 

False negative responses of 0.13-3.2% are an acceptable price. What are the chances of false positives slipping through Four alternative hypotheses are proposed for the VVV scheme (compare p to SL = 99.0, with p = j3, the type II error ) ... 

Interpretation While good batches of the quality produced (= 99.81% purity) have a probability of being rejected (false negative) less than 5% of the time, even if no replicates are performed, false positives are a problem an effective purity of /.t = 98.5% will be taxed acceptable in 12.7% of all cases because the found Xmean is 99% or more. Incidentally, plotting 100 (1 - p) versus /x creates the so-called power-curve, see file POWER.xls and program HYPOTHESlS.exe. 

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

Wagner et. al (46) studied 376 patients to evaluate the importance of identification of the myocardial-specific MB isoenzyme in the diagnosis of acute myocardial infarction. An attempt was made to determine the incidence of falsely positive (mb). No acute infarction was diagnosed in all patients in whom neither total CK nor the isoenzymes of LD indicated myocardial necrosis. Incidence of falsely negative (MB) was zero in 33 patients. They concluded that determination of the isoenzymes of CK provides both a sensitive and specific indication of acute myocardial infarction. 

Drugs can also Interfere with laboratory results by negating certain nonspecific oxidation and reduction reactions essential for the chemical assay. Penicillin, streptomycin and ascorbic acid are known to react with cupric Ion thus, false positive results for glucose may occur If a copper reduction method Is used. If the specific enzymatic glucose-oxidase method Is employed, ascorbic acid can cause a false negative result by preventing the oxidation of a specific chromogen In the reaction. 

The file Is used routinely In the laboratory at the National Institutes of Health In an attempt to explain abnormal test results The resident physicians affiliated with the Clinical Chemistry Service discuss the results with the patient-care physicians and determine If the results were due to the patient s clinical state or to a drug effect This close monitoring of test results has led to recognition of deficiencies In what Is believed are specific enzymatic procedures for the measurement of glucose and uric acid Likewise, the gualac procedure for occult blood In feces was found to yield false negative results under certain circumstances This has prompted the development of a more specific procedure (Jaffe et al unpublished) ... 

The use of animal models for depression has two main objectives. One is to provide a behavioural model that can be used to screen potential antidepressant treatments. For this, the behaviour does not have to be an animal analogue of depression all that is needed is for it to be consistently prevented by established antidepressant agents (i.e. no false negatives) but not by drugs which have no antidepressant effect in humans (i.e. no false positives). 

Analytical Methods Committee, Handling false negatives, false positives and reporting limits in analytical proficiency tests. Analyst, 122, 495, 1997. 

The Type I error is the error most often cited in the literature. In environmental monitoring, however, the Type II error may be more important. A false negative could create major problems for the environmental manager if it suggests that a cleanup is not necessary when in fact action levels are being exceeded. 

Ensure that the analytical methodology gives reliable results in terms of identity (absence of false-positive findings) and of absence (no false-negative findings) of the analyte(s). This requires processing of concurrent analytical quality control samples. 

Later in 1995, lUPAC came up with additional recommendations for the definition of LQD. Detection limit is defined as, The minimum detectable value of the net signal (or concentration) is that value for which the false negative error is given a. a ... 

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