Rodger D. Parker

The use and interpretation of commercial APC gene testing for familial adenomatous polyposis

BACKGROUND The use of commercially available tests for genes linked to familial cancer has aroused concern about the impact of these tests on patients. Familial adenomatous polyposis is an autosomal dominant disease caused by a germ-line mutation of the adenomatous polyposis coli (APC) gene that causes colorectal cancer if prophylactic colectomy is not performed. We evaluated the clinical use of commercial APC gene testing. METHODS We assessed indications for APC gene testing, whether informed consent was obtained and genetic counseling was offered before testing, and the interpretation of the results through telephone interviews with physicians and genetic counselors in a nationwide sample of 177 patients from 125 families who underwent testing during 1995. RESULTS Of the 177 patients tested, 83.0 percent had clinical features of familial adenomatous polyposis or were at risk for the disease-both valid indications for being tested. The appropriate strategy for presymptomatic testing was used in 79.4 percent (50 of 63 patients). Only 18.6 percent (33 of 177) received genetic counseling before the test, and only 16.9 percent (28 of 166) provided written informed consent. In 31.6 percent of the cases the physicians misinterpreted the test results. Among the patients with unconventional indications for testing, the rate of positive results was only 2.3 percent (1 of 44). CONCLUSIONS Patients who underwent genetic tests for familial adenomatous polyposis often received inadequate counseling and would have been given incorrectly interpreted results. Physicians should be prepared to offer genetic counseling if they order genetic tests.

A model for binary logic in biochemical systems

Abstract A model system involving a series of enzyme reactions, some of which display a sigmoid relationship between activity and substrate concentration, is discussed as a possible basis for binary logic in biochemical systems. Under the conditions described, a small change in the concentration of an initial substrate changes the activity of a terminal enzyme from nearly zero to nearly maximal activity, thus approximating a step-function or an on-off switch. Although the mechanistic basis for the sigmoid relationship is not limited to the allosteric model, allosterism is used for purposes of assigning a possible physical meaning to the parameters used in a sample calculation. The possible generation of square wave functions and timed pulses from the model is discussed.

The dynamics of the prevalence of chronic episodic disease

Abstract The often-cited equation prevalence equals incidence times average duration is not appropriate for diseases that run an episodic course. In this paper, we develop an alternative model; prevalence equals the product of incidence, average episode duration and average number of episodes. Heuristic models of the distribution of episode duration and of the distribution of number of episodes are proposed. The validity of these models is assessed for a chronic episodic disease—schizophrenic psychosis. The proposed models are recommended by their simplicity and the ease of interpretation of their parameters.

The use of human repetitive DNA to target selectable markers into only the human chromosome of a human-hamster hybrid cell line (AL)

We used the plasmid BLUR-8 that contains an 800-base pair (bp) sequence of human repetitiveAlu DNA in a cotransfection protocol to target the plasmids pSV2neo or EBO-pcD-leu-2 (hygro) into a single site of the sole human chromosome, number 11, of a Chinese hamster-human hybrid cell line (AL). The neo and hygro plasmids confer resistance to antibiotics G418 and hygromycin, respectively. Of the 33 cotransfected clones with single-site insertions, 1/13 without BLUR-8 and 6/20 with BLUR-8 were only in human chromosome 11. A frequency of insertion of 1/13 is not different than expected by chance (ϱ=0.3512). On the other hand, the probability that 6/20 insertions, as seen with BLUR-8, occurred by chance is low (ϱ=0.0003). We suggest that the human DNA sequences contained in BLUR-8 targeted insertions into only the human chromosome.

Parameters deducible from the kinetics of enzyme induction and repression

Abstract A model of enzyme induction and repression is derived in terms of the four microscopic parameters: transcription time of the message, ribosome scanning time over a message, ribosome scanning interval in an active polyribosome and the decay constant of the message. Ordinate scale invariant estimates of the second and fourth of these parameters are readily deduced from experimental data.

Analysis of mutant frequency curves and survival curves applied to the AL hybrid cell system

A model is presented for the statistical analysis of survival curves and mutant frequency curves for a hybrid cell system. The derivation of the model is given in the Appendix, and depends on simple assumptions about the distribution of insults, their repair, and the loss of a marker that is not rescued. A single formula (5) is found which relates a survival curve to the mutant frequency curve, i. e., the response curve for production of mutants per 10(5) survivors induced by a mutagen. The analysis is applied to loss of the a1 gene in AL-J1 hybrid cells submitted to Cesium gamma-rays. Previous experimental data using X-rays was reported by Waldren et al. (1986: Proc. Natl. Acad. Sci, USA 83, 4839.) Also, a derived formula (10), which predicts the probability that in a surviving cell a marker is lost and not rescued, will form the basis for testing the validity of the model in the future using new experimental data.

Evaluation of screening effectiveness

A methodology for evaluating the effectiveness of a screening program in terms of early detection of disease is presented. Formulas for predicting the effect of different screening intervals are developed. A case study using patient data from the Johns Hopkins Lung Project exemplifies how the method might be applied to cancer screening.

An illustration of the technique of canonical analysis.

The use of a multivariate statistical technique, canonical analysis, for the assignment of patients to diagnostic categories is presented. The classification of thyroid status using clinical findings is investigated to exemplify the application of the technique. Emphasis is placed on the stages in the data analysis that are generic in examining any set of medical data for the purpose of automatically classifying patients.

A study of the effects of fasting time on the one hour glucose tolerance test

Abstract The effect of time since last food intake upon the value of glucose one hour post challenge is examined on a large group of asymptomatic patients. A number of multivariate statistical techniques are employed, and after a series of determinations, the conclusion is reached that the time since last eating has a relatively marginal effect on the glucose tolerance test.

Comparing a Scheduled Process with an Analogous Poisson Process

The generating function of a queue in which n arrivals occur at fixed times, of equal intervals apart, and in which the service times are independently and identically distributed exponentially is derived in recursive form. The state probabilities are calculated explicitly for n = 1. An analogous recursion formula for the generating function of a related Poisson process is used to estimate whether the scheduled process may be approximated by a Poisson one. In no instance is the approximation a good one.