Linear mixed-effects analysis of longitudinal measurements of

Burdjalov score with assessment of the impact of Morphine and

Gestational age

The data
The data comprises 252 complete observations over 51 subjects. The observed variables are time
since birth (days), Burdjalov score, morphine treatment and gestational age (weeks).

The time since birth ranges from 1 day to 114 days. Due to extreme dispersion of observations
(extreme values only appear once in the data, which can cause stability problems in the analysis)
natural logarithm of time will be considered. The following graph shows the Burdjalov scores vs.
time for all subjects, with different colours for morphine treatment. In general, the Burdjalov score
seems to increase with time, and administration of morphine corresponds to lower scores.
Analysis
Preliminary analysis
A simple linear regression of Burdjalov score vs. (log) time shows that it’s important to explicitly
model the longitudinal nature of the data (repeated measures on the same subject at different time
points.) Boxplots of the regression residuals by subject show the need for a subject effect in the
model.

We next fit a series of linear regressions of Burdjalov score vs. (log) time for each subject (only 46
subjects could be used in this analysis since 5 subjects only have one observation, and we require at
least two observations per subject). The following graph shows that there is extreme inter-subject
variability both in the intercept and slope of the model. This calls for a more complex model in which
both the intercept and model coefficients are random rather than fixed. Note that neither morphine
nor gestational age information have been used in these simple models, since at this stage we are
only interested in assessing the appropriateness of a longitudinal model.
Linear mixed-effects models
We now consider a longitudinal model where both the intercept and time coefficient are normal
random variables. We further adjust for gestational age and morphine. It is also of interest to assess
whether gestational age and/or morphine enter the model as fixed effects or random effects. Three
models were fitted, corresponding to different hypotheses as shown in the following table:

Random effect df AIC

Intercept+Time 8 1012.05
Intercept+Time+Morphine 11 967.47
Intercept+Time+Gestational age 11 1018.05

where df denotes the number of parameters (degrees of freedom) and AIC is the Akaike Information
Criterion, an information-theoretic measure of the trade-off between model complexity and model
fit (the lower the AIC, the better the model.) The best model is therefore the one with morphine as
an additional random effect.
In the following table we report the model parameter estimates, the corresponding F statistics, and
the standard deviation of the random effects:

Parameter Standard deviation F p-value

of random effect
Time 2.055 0.632 413.325 <0.0001
Morphine -2.94 2.815 270.960 <0.0001
Gestational age 0.338 - 9.686 0.0031

We now assess whether the model assumptions are satisfied. The two fundamental assumptions
are:

1- The within-group errors are normally and independently distributed with zero mean and
constant variance
2- The random effects are normally distributed with mean zero and are independent for
different groups

The following graph shows boxplots of residuals per subject. This graph should be compared with
the previous residual graph of the naïve linear model. The boxplots now cluster around zero, and
they are much shorter, denoting a smaller variation. This suggests that the new model describes
better the observation variation in the data.
In the next graph we show the quantile-quantile plot of the residuals vs. the standard normal. The
assumption of normality seems reasonable although there is some asymmetry.

The last graph shows the quantile of the estimated random effects in the model. In all cases, no
strong deviation from normality can be detected.
Conclusions
We have modelled the longitudinal measurements of the Burdjalov score and its dependence on
gestational age and administration of morphine. The model suggests heterogeneity amongst
subjects of time evolution of the Burdjalov score, and the effect of morphine on subjects. On
average, the Burdjalov score increases with time, and with baseline gestational age; but decreases
with morphine administration.