Computational analysis of CFSE proliferation assay.

CFSE based tracking of the lymphocyte proliferation using flow cytometry is a powerful experimental technique in immunology allowing for the tracing of labelled cell populations over time in terms of the number of divisions cells undergone. Interpretation and understanding of such population data can be greatly improved through the use of mathematical modelling. We apply a heterogenous linear compartmental model, described by a system of ordinary differential equations similar to those proposed by Kendall. This model allows division number-dependent rates of cell proliferation and death and describes the rate of changes in the numbers of cells having undergone j divisions. The experimental data set that we specifically analyze specifies the following characteristics of the kinetics of PHA-induced human T lymphocyte proliferation assay in vitro: (1) the total number of live cells, (2) the total number of dead but not disintegrated cells and (3) the number of cells divided j times. Following the maximum likelihood approach for data fitting, we estimate the model parameters which, in particular, present the CTL birth- and death rate "functions". It is the first study of CFSE labelling data which convincingly shows that the lymphocyte proliferation and death both in vitro and in vivo are division number dependent. For the first time, the confidence in the estimated parameter values is analyzed by comparing three major methods: the technique based on the variance-covariance matrix, the profile-likelihood-based approach and the bootstrap technique. We compare results and performance of these methods with respect to their robustness and computational cost. We show that for evaluating mathematical models of differing complexity the information-theoretic approach, based upon indicators measuring the information loss for a particular model (Kullback-Leibler information), provides a consistent basis. We specifically discuss methodological and computational difficulties in parameter identification with CFSE data, e.g. the loss of confidence in the parameter estimates starting around the sixth division. Overall, our study suggests that the heterogeneity inherent in cell kinetics should be explicitly incorporated into the structure of mathematical models.

Community-based screening by colonoscopy or computed tomographic colonography in asymptomatic average-risk subjects.

OBJECTIVES: Visualizing the entire colorectum in screening is an advantage of colonoscopy, and also computed tomographic (CT) colonography, another potentially suitable screening test. Our objective was to compare screening CT colonography and colonoscopy in an asymptomatic average-risk population, and to determine whether providing a choice of tests increased participation. METHODS: One thousand and four hundred subjects from the general community, randomly selected from the parliamentary electoral roll, were allocated one of three screening groups: colonoscopy, CT colonography, or a choice of these tests, and were sent an institutional letter of invitation. Those with symptoms, colorectal cancer in first-degree relatives, or colonoscopy within 5 yr were ineligible. Outcome measures were participation, acceptability of screening, and yield for advanced colorectal neoplasia in participants. RESULTS: Of the subjects, 24.9% were ineligible; the overall participation rate was 18.2% (184/1,009). Participation in each screening group was not different. Both tests were accompanied by the same high levels of acceptability; most participants found colonoscopy (87%) and CT colonography (67%, p < 0.001) less unpleasant than expected. About 29% (26/89) CT colonography subjects had a positive screening test. The yield of advanced colorectal neoplasia was 8.7% (95% CI 5-14%), with no difference in yield between tests. CONCLUSION: Colorectal neoplasia screening by colonoscopy or CT colonography was associated with modest participation, high levels of acceptability, and similar yield for advanced colorectal neoplasia. Providing a choice of test did not increase participation.

Colorectal neoplasia screening with CT colonography in average-risk asymptomatic subjects: community-based study.

PURPOSE: To evaluate computed tomographic (CT) colonography as a screening tool for average-risk asymptomatic subjects with regard to participation, acceptability, and safety. MATERIALS AND METHODS: CT colonography for colorectal neoplasia screening was offered to 2,000 subjects aged 50-54 and 65-69 years. Only asymptomatic subjects at average risk of colorectal neoplasia were enrolled. Participants underwent CT colonography followed by colonoscopy if CT colonography findings showed any polyps. Acceptability was measured with a 100-point (0, most favorable; 100, least favorable) visual analogue scale (VAS). Chi2 statistic was used to compare participation rates among subgroups. Safety of CT colonography was evaluated by recording all important adverse events. RESULTS: A total of 1,452 subjects were eligible for screening. The adjusted participation rate was 28.4%. Participation was higher in younger subjects and in those from a high socioeconomic region. Major reasons for nonparticipation were insufficient time and perceived good health. Median VAS scores for pain, general satisfaction, embarrassment, and willingness to repeat screening were 13, 6, 8, and 5, respectively. Most subjects found CT colonography better than (60%) or same as (32%) expected. Ninety-three (27.4%) of 340 subjects were referred for colonoscopy, with polyps found in 67 (positive predictive value, 0.73). By adopting criteria that a positive finding at CT colonography is that of a single polyp larger than 5 mm or multiple polyps larger than 2 mm, 14% of CT examinations would have led to colonoscopy; 5.7% of CT findings were false-positive, with no significant impairment in large polyp detection. There were no important adverse events related to CT colonography, although four subjects had syncope or presyncope related to bowel preparation. CONCLUSION: Community-based colorectal neoplasia screening with CT colonography was accompanied by a participation rate that compares favorably with that of similar screening programs. CT colonography was highly acceptable to participants.

Influences on participation in a community-based colorectal neoplasia screening program by virtual colonoscopy in Australia.

OBJECTIVE: To determine the effect of certain personal and health behaviour characteristics on participation in a community-based colorectal neoplasia (CRN) screening program using virtual colonoscopy. METHODS: The study population comprised randomly selected subjects from the State electoral roll; screening by virtual colonoscopy was offered through letter of invitation. For non-responders, a further invitation was sent a month later. Non-response after a further month led to subjects being considered non-participants. Non-participants were contacted by letter to complete a structured questionnaire; participants completed a similar questionnaire immediately after their screening virtual colonoscopy. RESULTS: Discussing the invitation to screening with someone else increased the likelihood of participation by 63% (prevalence ratio 1.63, 95% CI 1.38-1.93); knowing someone with cancer increased the likelihood of participation by 23% (PR 1.23, 95% CI 1.07-1.42). Among participants who discussed screening with another individual, the spouse was the most common (71%). Subjects who were single were less likely to participate (PR 0.79, 95% CI 0.67-0.94). The strongest reported influence for participation was information provided in the letter of invitation (29.8%). The most common reasons for non-participation were lack of time and perceived good health. CONCLUSIONS AND IMPLICATIONS: This study suggests that a simple strategy to facilitate participation is to encourage subjects to discuss screening with others; further, to recognise that this may be most difficult for those who are single. Information provided to subjects prior to screening positively contributes to participation.