Model comparison.

<p>Comparison of each hypothesis against the best fitting model consisting of hypotheses A1, B1, C1, D1 and E1. Decibans >10 are strong evidence against a hypothesis (Equation 26).</p

Epo oscillations.

<p>Testing diurnal oscillations in Epo data.</p

Model fits.

<p>Fits of best fitting model to RBC concentrations and reticulocyte proportions of individual mice of the main experiment. A: First 14 days, and B: all data. Grey regions are 95% posterior predictive intervals (95% of data should lie within this region), and solid lines are median solutions constructed from the 10⁴ samples of the posterior distribution.</p

Standardised residuals.

<p>Assessment by standardised residuals of the model consisting of hypotheses A1, B1, C1, D1, E1 fitted to all data of the main experiment. Top panel: RBC concentration, bottom panel: reticulocyte proportion. Each cross represents the standardised residual of a time point for an individual mouse. These have an approximately normal distribution with mean 0 and variance 1. The solid line is the mean of the standardised residuals at each time point. The dashed lines define the approximate interval (Bonferroni corrected for multiple tests) within which we expect the mean to lie 95% of the time if the model were true. Note the nonlinear .</p

Predicted RBC age distributions.

<p>Prediction of circulating RBC age distribution just before, just after, and at various days after, PHZ treatment for mouse 6. The black line shows the estimated median age distribution and the grey region the 95% posterior predictive interval calculated from the samples of the posterior distribution of the model consisting of hypotheses A1, B1, C1, D1, E1. On day 0 the age distribution is in equilibrium made up of about 1% reticulocytes. All RBCs are aged with PHZ treatment causing an approximately 30% drop in RBC concentration, and a higher than normal clearance rate for about 7 days. Anaemia induces early release of reticulocytes from bone marrow (day 5) and increased reticulocyte production. Random clearance of RBCs prevents a large drop in RBC concentration about 50 days after PHZ treatment (day 40). The system returns to equilibrium after about day 60.</p

Variables and parameters used in the mathematical models.

<p>Variables and parameters used in the mathematical models.</p

Control experiments.

<p>Mean±1sem of RBC concentration (top panel) and reticulocyte proportion (bottom panel) of main experiment (red dotted lines, same as in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000416#pcbi-1000416-g001" target="_blank">Figure 1</a>) sampling controls (black dot-dashed lines), individually-housed, PHZ-treated controls (blue dashed lines) and group-housed, PHZ-treated controls (green solid lines). Lines are slightly offset from each other to reveal extent of error bars.</p

Hypothesis testing.

<p>A: Hypothesis A2: polycythemia not reducing production rate does not capture RBC and reticulocyte dynamics after day 60 (shown for mouse 6). B: Hypothesis A1: Production rate varies almost linearly with anaemia even allowing for an exponential relationship (shown for mouse 6). C: Hypothesis C1: reticulocyte release rate is exponentially related to anaemia (shown for mouse 6). D: Hypothesis D2: fixed RBC lifespan does not capture RBC dynamics. E: Hypothesis D3: unlimited RBC lifespan does not capture RBC dynamics.</p

Parameter estimates.

<p>Marginal distributions of parameters of model consisting of hypotheses A1, B1, C1, D1, and E1 for main, and housing control experiments.</p

RBC and reticulocyte dynamics.

<p>Individual mouse data (left panels) and mean±2sem (right panels) of RBC concentration (top panels) and reticulocyte proportion (bottom panels) of the 10 mice in the main experiment for A: first 14 days, B: full 114 days. Inset expands reticulocyte proportion from days 15 to 114.</p