Predicted incidence rates for men (full lines) and women (dashed lines) from the two path model TP4 (red) and the contributions of the CIN pathway (green) and the MSI path (blue dot-dashed line, both sexes) in 14 intervals of attained age from 20–25 yr to 85–90 yr.

<p>Predicted incidence rates for men (full lines) and women (dashed lines) from the two path model TP4 (red) and the contributions of the CIN pathway (green) and the MSI path (blue dot-dashed line, both sexes) in 14 intervals of attained age from 20–25 yr to 85–90 yr.</p

MLE with 95% CI of the excess absolute risk (EAR) per 10⁴ PY and of the excess relative risk (ERR) for women (panels A, C) and men (panels B, D), exposed to 1 Gy at age 30 (born in 1915) for the descriptive models DERR and DEAR [28] (black), and the two path model TP4 (red).

<p>Only MLE are shown for pathway-specific excess risks pertaining to MSI (blue) and CIN (green).</p

Estimates for baseline rates (unit yr⁻¹ per cell) of cell-kinetic processes in the two path model TP4.

<p>Estimates for baseline rates (unit yr⁻¹ per cell) of cell-kinetic processes in the two path model TP4.</p

Summary of colon cancer incidence data in the LSS cohort from 1958–1998 for dose groups with shielded air kerma <4 Gy, 95% percentiles of frequency distribution for person years in brackets.

<p>Summary of colon cancer incidence data in the LSS cohort from 1958–1998 for dose groups with shielded air kerma <4 Gy, 95% percentiles of frequency distribution for person years in brackets.</p

Predicted share of cases in the MSI pathway calculated from the two path model TP4 for the full follow-up period 1958–1998 and periods 1958–1980, 1981–1998.

<p>Predicted share of cases in the MSI pathway calculated from the two path model TP4 for the full follow-up period 1958–1998 and periods 1958–1980, 1981–1998.</p

MLE (95% CI in brackets) of the excess relative risk (ERR) and the excess absolute risk (EAR) per 10⁴ PY for persons of attained age 70, exposed to 1 Gy at age 30 (born in 1915) from the descriptive models DEAR and DERR [28] and the two path model TP4.

<p>MLE (95% CI in brackets) of the excess relative risk (ERR) and the excess absolute risk (EAR) per 10⁴ PY for persons of attained age 70, exposed to 1 Gy at age 30 (born in 1915) from the descriptive models DEAR and DERR <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024-Preston1" target="_blank">[28]</a> and the two path model TP4.</p

Relative risk (RR) with 95% CI in colon dose groups 0.005–0.25 Gy and>0.25 Gy compared to dose group <0.005 Gy.

<p>Relative risk (RR) with 95% CI in colon dose groups 0.005–0.25 Gy and>0.25 Gy compared to dose group <0.005 Gy.</p

Conceptual model for colon cancer carcinogenesis from normal epithelium to carcinoma with two molecular pathways of genomic instability: microsatellite instability (MSI, top, blue) and chromosomal instability (CIN, bottom, green).

<p>Greek symbols denote rates of mutation or hypermethylation (ν) as genetic alterations successively on both alleles, and rates of symmetric cell division (α) or inactivation (β); genetically altered cells are created by asymmetric cell division (marked by a pair of straight and bent arrows, for normal stem cells only the straight arrow is used to account for homeostasis); the rate λ_CIN of destabilizing events in CIN (pair of green arrows) depends on birth cohort; in large adenoma at least one malignant cell leads to a tumor, which is detected after a fixed lag time t_lag = 5 yr; jagged bolts (yellow) point to radiation targets of the preferred two path model TP4.</p

MLE, SE from a parabolic approximation around the minimum of the likelihood function, and ΔCI_LP from the actual likelihood profile in the standard σ range for the identifiable parameters of the two path model TP4 with relation to biological parameters, superscript m,f indicates sex-dependence, radiation-response parameters r_I and r^m_CIN on dose <i>D</i> are given for an exposure duration of 1 week, rate λ_CIN(b) of destabilizing events in CIN increases exponentially with birth year <i>b</i> = 1945.6–<i>e</i> (age at exposure).

a<p>log-transformed.</p><p>MLE, SE from a parabolic approximation around the minimum of the likelihood function, and ΔCI_LP from the actual likelihood profile in the standard σ range for the identifiable parameters of the two path model TP4 with relation to biological parameters, superscript m,f indicates sex-dependence, radiation-response parameters r_I and r^m_CIN on dose <i>D</i> are given for an exposure duration of 1 week, rate λ_CIN(b) of destabilizing events in CIN increases exponentially with birth year <i>b</i> = 1945.6–<i>e</i> (age at exposure).</p

Deviance and ΔAIC values for the descriptive and mechanistic models of the present study, ΔAIC is defined as the difference in AIC to the preferred two path model TP4.

a<p>from Preston et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024-Preston1" target="_blank">[28]</a>.</p>b<p>baseline model equivalent to the three-stage model of Meza et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024-Meza1" target="_blank">[19]</a>, see SI, Table S2 and Figure S1 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024.s001" target="_blank">File S1</a>.</p>c<p>inspired by Nowak et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024-Nowak1" target="_blank">[16]</a>, derived from Little and Li <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024-Little1" target="_blank">[17]</a> (their <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone-0111024-g002" target="_blank">Figure 2</a>), see SI, Table S3 and Figure S2 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024.s001" target="_blank">File S1</a>.</p>d<p>Table S4 and Figure S3 in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0111024#pone.0111024.s001" target="_blank">File S1</a>.</p>e<p>preferred model of the present study.</p><p>Deviance and ΔAIC values for the descriptive and mechanistic models of the present study, ΔAIC is defined as the difference in AIC to the preferred two path model TP4.</p