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The entry count $N_s(t)$ counts jumps of a continuous-time Markov chain into state $s$ by time $t$, excluding initial occupation. It is a counting process. For homogeneous transition intensities, its mean has derivative ${\sum }_{i\ne s}{p}_{ri}(t)q_{is}$ conditional on initial state $r$, so its expected value is the sum of incoming rates times the expected occupation times of a continuous-time Markov chain. This density is an expected count rate, not necessarily a normalized probability density function.

Global balance equates total stationary incoming and outgoing transition intensities at each state. Detailed balance for a continuous-time Markov chain is sufficient but stronger: it equates each pair separately.

A positive transition intensity can be modeled as $q_{rs}(t\mid z)=\exp ({\theta }_0+{\theta }^{T}z(t))$. A unit increase in a fixed covariate multiplies the intensity by $e^{{\theta }_j}$. A changing covariate generally gives a time-dependent generator matrix.

The permitted transitions form the following diagram. Each arrow is labelled by its fitted transition intensity in units of inverse years; the absence of an arrow is a structural restriction, not an estimated small effect.

State 1 can move directly to 2, 3 or 5; state 2 can move to 4 or 5; state 3 can move to 4 or 5; and state 4 can move only to 5. There are no recovery transitions, and state 5 is an absorbing state. The rates of leaving the four living states are the sums of their outgoing arrows:The diagonal generator entries are their negatives, so every row of $Q$ sums to zero. These diagonal entries are not arrows or negative event rates. For example the direct $1\to 5$ rate is $0.004$ per year, while death after reaching another state can occur at a much larger rate. The printed fit has no covariates on the intensities, so it estimates one pooled rate system and contains no treatment-effect comparison, despite the trial's treatment randomization. The reported $-2\ell$ describes the fitted likelihood level; by itself it is not a goodness-of-fit test without a reference or competing model.

The transition matrix over five years is $P(5)=e^{5Q}$. Its first row conditions on starting in state 1. The displayed approximate probabilities mean that, five years later, about 65% remain disease-free, 6% have local recurrence only, 10% have distant metastasis only, 2% have both, and 16% have died. They are probabilities of the states occupied at five years; they are not the probabilities of the next jump destinations or annual transition intensities. In particular the positive probability of state 4 does not require a direct $1\to 4$ arrow: the paths $1\to 2\to 4$ and $1\to 3\to 4$ contribute to it. The probability of death includes deaths after any allowed sequence of intermediate states.

The printed row sums to $0.99$ rather than one because the entries are approximate; an exact stochastic transition row sums to one. Exponentiating the displayed three-decimal generator gives approximately $(0.65377,0.06490,0.09775,0.02532,0.15826)$, illustrating that the edited, low-precision table should not be treated as an exact matrix exponential of its separately rounded rates.

State 5 is an absorbing state, so once entered it can never be left. Its generator row is zero, and the last row of every positive-time transition matrix is thereforeThis explains all four leading zeroes in the printed last row.

Use the time-homogeneous continuous-time multi-state model displayed in part ii. Write $Z(t)$ for the state at time $t$, $Q=(q_{rs})$ for its generator matrix, andFor $r\ne s$, $q_{rs}={\lim }_{h\downarrow 0}{p}_{rs}(h)/h$ is the transition intensity, and $q_{rr}=-{\sum }_{s\ne r}{q}_{rs}$. Condition on the observed initial state, and treat the clinic observation process and administrative end of follow-up as noninformative. A panel-observed interval contributes its transition probability, not the density of a jump at the examination date; the transitions inside that interval need not have been observed.

For the first patient, the two clinic intervals contribute $p_{11}(2)p_{13}(2)$. The subsequent death is observed at elapsed time $u=0.2$ after the last clinic state, so its contribution is the conditional death-time densityThe equality uses the permitted directions: starting from state 3, only living states 3 and 4 can be occupied before death. To obtain this density directly, survival in a living state $s$ until time $u$, followed by death in $(u,u+du)$, has probability $p_{3s}(u)q_{s5}du+o(du)$; add over the unobserved state $s$. Hence the mixed panel and exact-death likelihood contribution isIt includes the possibility of an unrecorded transition $3\to 4\to 5$ between the last clinic visit and death. Keeping only $p_{33}(0.2)q_{35}$ would exclude that allowed history, while $p_{35}(0.2)$ would be the probability of death by that time rather than the density of death at that time. With dates recorded in whole days, an exact interval-likelihood treatment integrates this density over the relevant day; the density formulation is its fine-time approximation.

For the second patient, the three successive intervals with state 1 at both ends, then the interval ending in state 2, and the last interval remaining in state 2 give the panel-observed multi-state likelihoodThere is no additional death contribution after the final administrative observation. Each likelihood contribution already accounts for being alive in the observed state at that visit. For independent patients their joint conditional likelihood contribution is $L_1{L}_2$.

For an explicit form, put ${\lambda }_r=-q_{rr}$. Irreversibility givesandThese formulas follow by integrating the density of the one possible intermediate jump time; at equal exit rates the limiting expression is $q_{rs}u{e}^{-{\lambda }_{r}u}$. ThusUsing the displayed fitted rates as numerical values gives $g_{35}(0.2)\approx 0.289314$ per year, $L_1\approx 0.017596$ per year and $L_2\approx 0.016048$, providing a check of the probability-versus-density distinction.

For patient $h$, let $Z_h(t)\in \{1,2,3\}$ be the fatigue state at time $t$ years since study entry. Let the covariate vector be $z=(s,d,a,g{)}^T$, representing the sex indicator, arthritis duration in years, HAQ disability score and haemoglobin measurement. Conditional on these covariates, the continuous-time multi-state model has the Markov property and generator matrixEach allowed transition intensity has its own log-linear transition intensity model, $q_{ij}(z)=\exp ({\eta }_{ij}+b_{ij}^{T}z)$. The zero entries exclude direct instantaneous jumps between mild and severe states, and the diagonals enforce zero row sums.

To express the estimates correctly, the printed intensities are evaluated at the sample covariate means $\bar{z}$, not at $z=0$. Order the allowed transitions as $12,21,23,32$. Their estimates arewith rows indexed by that transition order and columns by $s,d,a,g$ inEquivalently, the uncentred intercept is ${\hat{\eta }}_{ij}=\log {\hat{q}}_{ij}(\bar{z})-{\hat{b}}_{ij}^T\bar{z}$. The means are not printed, so the displayed rates cannot be treated as numerical zero-covariate intercepts.

The assumptions are independent patients conditional on their covariates; correctly observed fatigue states; no unmodelled history dependence once current state and covariates are known; positive adjacent-state intensities with the specified exponential covariate dependence and no interaction terms; and a noninformative observation and censoring mechanism for the conditional state-process likelihood. With fixed covariates the rates are homogeneous in time and holding times are exponential. Covariates updated at visits are treated as piecewise constant between observations, so each such interval has a constant generator, a piecewise-constant covariate approximation. In particular this is an approximation if a quantity such as duration changes continuously between visits.

For observations $Z_h(t_{hk})=s_{hk}$, conditioning on the initial observed state, the panel-observed multi-state likelihood is a product over patients and intervals ofwhere $z_{hk}$ is the covariate value held over that interval. Multiple unobserved jumps within an interval are integrated out by this transition matrix. For example, a mild state followed by a severe state can have positive likelihood despite $q_{13}=0$, because an unobserved moderate state can intervene. The panel observations within a patient are not independent; it is the Markov property that justifies multiplying conditional transition probabilities. The piecewise-constant handling of changing covariates is specified in the msm model documentation.

The fitted continuous-time multi-state model allows only adjacent fatigue-state jumps. Its four transition intensities, in reciprocal years, are shown here:

In state $2$, the total exit intensity is ${\lambda }_2=q_{21}+q_{23}=0.4684+0.3835=0.8519$. By the holding time law for a continuous-time Markov chain, the time until the next jump has an exponential distribution with this rate. ThereforeThe printed interval for $q_{22}=-{\lambda }_2$ gives the interval $(0.7219,1.005)$ for ${\lambda }_2$. Taking reciprocals reverses the endpoints, so the transformed $95\%$ confidence interval for the mean holding time isFor the next jump's destination, competing outgoing intensities giveIndeed the density of a first jump to $1$ at time $t$ is $q_{21}{e}^{-{\lambda }_{2}t}$; integrating gives the ratio above. This is a conditional next-jump probability, not a transition probability of being mild at a fixed later visit.

For the mild-to-moderate transition intensity, an increment $\Delta$ in a single covariate, with the others held fixed, gives the multiplicative ratio $\exp (b_{12,k}\Delta )$. Of the four printed effects on this transition, sex and HAQ have $95\%$ confidence intervals excluding zero on the log-intensity scale.

With male coded $1$ and female coded $0$, the estimated hazard ratio for males relative to females isThus, conditional on currently being mildly fatigued and on the other covariates, males have an estimated mild-to-moderate transition intensity about $54\%$ lower than females. The conclusion concerns this particular instantaneous transition, rather than a general $54\%$ reduction in fatigue probability.

For a one-point increase in HAQ, indicating greater physical disability, the estimated intensity multiplier isGreater disability is therefore associated with a substantially faster mild-to-moderate transition, after adjustment for sex, arthritis duration and haemoglobin. Both conclusions use the specified log-linear transition intensity model and the nominal individual $95\%$ intervals. Arthritis duration and haemoglobin have intervals including zero for this transition, so their effects here are not statistically significant at $5\%$; this says neither that their effects are zero nor that they are insignificant for all other transitions.

Use the three-state competing risks model shown below. State 0 is alive after surgery, state 1 is dead from lung cancer, and state 2 is dead from other causes. Both death states are absorbing. Study censoring is an observation mechanism, not a biological transition to a fourth state.

For treatment $z=0$ (radiotherapy) or $z=1$ (chemotherapy), define the transition intensityThe fitted Cox proportional-hazards models areHere ${\hat{\lambda }}_{10}$ and ${\hat{\lambda }}_{20}$ represent the estimated baseline cause-specific hazards for radiotherapy. More formally, the baseline estimates can be expressed as cumulative hazard measures with increments $d_k(t)/{\sum }_{i\in R(t)}{e}^{{\hat{\gamma }}_k{z}_i}$, rather than ordinary smooth functions. All outgoing intensities from states 1 and 2 vanish, and $q_{00}=-(q_{01}+q_{02})$. The treatment hazard ratios are 3.7111 and 1.8045 respectively. This model describes the two observed causes of death, not identifiable latent failure times after death has already occurred.

Let $q_{rs}$ be the transition intensity from state $r$ to $s$, and let $Q$ be the transition intensity matrix, with $q_{rr}=-{\sum }_{s\ne r}{q}_{rs}$. For a continuous-time multi-state model with the time-homogeneous Markov property, the transition probability matrix is $P(u)=e^{uQ}$, with entry $p_{rs}(u)$. Condition on each recorded initial state. Panel visits contribute transition probabilities; an exact entry into the absorbing death state contributes a statistical probability densityThis mixed panel and exact-death likelihood sums over the living state just before death. It accounts for survival until the event; replacing its final factor by $p_{r3}(u)$ would count deaths throughout the interval.

Using the actual visit times recovered from the PDF, the three individual likelihood contributions areHere $g_{23}$ means $g_{r3}$ with $r=2$, not a transition probability. Subjects 8 and 9 supply no event-density factor after their last panel observation. Assume independent subjects and noninformative examination and censoring times; conditional on their observation schedule, its distribution supplies no additional statistical parameter-dependent factor. The patients' covariates can be incorporated by using their own $Q_i$ in these same expressions.

For the progressive structure used in the subsequent output, put $a=q_{12}$, $b=q_{13}$, $c=q_{23}$ and $\lambda =a+b$. The progressive illness-death model permits no recovery, soWhen $\lambda =c$, the continuous limit is $p_{12}(u)=au{e}^{-cu}$. Thus the likelihood contributions simplify toIntermediate unobserved disease transitions remain integrated into each panel transition probability.

Under $H_0$, the seven free covariate coefficients all equal zero. The likelihood-ratio test statistic isThe larger fit has ten free statistical parameters, compared with three in the constant-rate fit, so the reference chi-squared distribution has seven statistical degrees of freedom. Its 95th percentile is $14.06714$. Therefore reject $H_0$ at 5%; the p-value is approximately $0.0043$, and the covariate model is preferred. The two constrained sex coefficients add no free statistical parameters.

For the dementia-to-death arrow, the hazard ratio for higher versus lower education is $e^{-1.490}=0.2254$, with approximate 95% confidence interval $(e^{-2.547},e^{-0.4327})=(0.0783,0.6488)$. Thus higher education is associated with a roughly 77.5% lower fitted death transition intensity, conditional on diagnosis age; the interval excludes one. This is an observational association and is not a direct multiplicative statement about death probability.

Each additional year of age at diagnosis multiplies the dementia-to-death transition intensity by $e^{0.07984}=1.0831$, with confidence interval $(e^{-0.007765},e^{0.1674})=(0.9923,1.1822)$. The estimate suggests an increase, but the interval includes one, so this individual age coefficient is not significant at 5%. Sex has hazard ratio one for this transition by the model's imposed constraint. The output supplies no estimated sex effect or test of that constraint for this arrow. The nonzero sex coefficient for $1\to 2$ must not be mistaken for a sex effect on $2\to 3$.

Let $z_i=(S_i,E_i,A_i{)}^T$ contain sex, the education indicator, and age at diagnosis. Write $\overline{z}$ for the sample means. The output's baseline transition intensities are evaluated at those means, so use the centred log-linear transition intensity modelThe full transition intensity matrix isThe fitted centred baselines are $(q_{12},q_{13},q_{23})(\overline{z})=(0.1821,0.0126,0.0450)$, and fitted slope vectors in sex–education–age order areThe two sex coefficients displayed as zero are fixed by the specified constraints; they are not estimated to be exactly zero. There are three free baseline transition intensities and seven free covariate slopes. The sample means are not printed, so uncentred intercepts at $z=0$ cannot be recovered numerically from this output.

Conditional on fixed covariates, subjects follow independent, correctly classified continuous-time multi-state models obeying the time-homogeneous Markov property, with $P_i(u)=e^{u{Q}_i}$. The progression is irreversible and death absorbing, with constant transition intensities during follow-up for each subject. In particular, the model uses fixed age at diagnosis rather than attained age. It assumes noninformative observation and censoring, and treats death times as exact through the mixed panel and exact-death likelihood. The Markov property rules out an additional effect of elapsed time in the current state after conditioning on it and the recorded predictors.

The fitted progressive illness-death model has three allowed arrows: $1\to 2$ with estimated transition intensity $0.1849$, $1\to 3$ with $0.01935$, and $2\to 3$ with $0.06143$, all in years${}^{-1}$. State 3 is an absorbing state, and state 2 has no return arrow.

Once in state 2, the holding time has an exponential distribution with rate $q_{23}$, so the mean holding time from a transition intensity matrix isApply a confidence interval for an inverse rate to the printed rate interval $(0.03552,0.1063)$: since inversion reverses order, the approximate 95% interval for the mean isThe time-homogeneous Markov property makes the future depend only on the current state; the exponential distribution also has the memoryless property. For a person currently in state 2,Equivalently, $p_{22}(2)=p_{22}(1{)}^2\simeq 0.9404163^2$. Thus the fitted two-year death probability is approximately 11.6%.

There are three free transition intensities: progression, death from the initial state, and death from the advanced state. In the three-state illness-death model, state 3 is an absorbing state, and there is no recovery transition.

Writing $a=q_{12}$, $b=q_{13}$ and $c=q_{23}$, with all three nonnegative, the transition intensity matrix isEach diagonal entry is minus the sum of the row's outgoing transition intensities, rather than an additional unknown parameter. A continuous-time multi-state model with these rates describes the severity labels in the observations; an explicit cured state would require a richer state space.

In a time-homogeneous continuous-time Markov chain, a state's holding time is exponential with rate equal to its total outgoing transition intensity. Converting the specified times to months givesThe exit-type probability follows by dividing its transition intensity by the total exit rate. ThereforeThese are starting values for numerical estimation, rather than further observations or constraints on the final fitted rates.