Methodological considerations and risk of bias

The last few years have seen the development and implementation of PROMIS (Patient-Reported Outcomes Measurement Information System), which is an initiative by the US National Institute of Health (NIH). The goal was to develop a "psychometrically validated, dynamic system to measure patient reported outcomes efficiently in study participants with a wide range of chronic diseases and demographic characteristics"(HealthMeasures, 2020).

PROMIS measures cover physical, mental, and social health. These measurements have now found use in research in cerebral palsy and should be considered for future studies with aims similar to the ones presented in this thesis.

4.3.2 Papers I & II

A mailed survey would have been a more typical approach to data collection in papers I and II. Benefits with a mailed survey would possibly, but not definitely, include a higher

inclusion rate because of the relative ease of answering the questions at home instead of together with the examiner. The benefits of having a data collection through direct contact with one or a few investigators include that items that the participant feel are unclear can be clarified (increasing accuracy), that the same approach to the items is used consistently (increasing accuracy and decreasing differential misclassifications) and that incongruent responses from the participant can be addressed (again, increasing accuracy).

While the recruitment approach targeted an age-specific total population, the final sample was a lesser proportion: 32% of the entire target population or 44% of those where contact could be made. Distribution of sex, GMFCS-levels, and prevalence of epilepsy and ID all matched expected proportions, which gives strong evidence of a representative sample. There is however still the possibility that those who agreed to participate differ in some respects compared to those who did not. The main concern is that of selection bias(Hernan et al., 2004), i. e. that the possibility of being included in the study is associated with the outcome.

To put it in an example: that those who participate tend to have higher or lower HRQoL, or better or worse social outcomes, than those who did not participate. This is a particularly high risk in convenience samples. The fact that the present sample of young adults, which was not a convenience sample, had expected frequencies on the most central variables and

comorbidities down-plays this risk but does not eliminate it. There are examples where it has been shown that more pronounced disease severity is coupled with an increased willingness to participate in cross-sectional studies (Apfelbacher et al., 2009). If this bias is present in this

data collection it would mean that the direction of the bias is that of overestimation of

‘disease severity’, in this study translated into that health status, pain, fatigue and social outcomes are in fact better in young adults with CP than what the present results show.

The use of proxy-responders enabled the study to include young adults with CP within all levels of functioning. This was a strength of the study. However, the use of proxies introduces risks of bias. As discussed in section 4.1.3.1, proxies tend to underestimate

HRQoL. This could mean that HRQoL could be even higher than reported in those who were assisted by proxies. And as discussed in section 4.1.3.2, proxies tend to underestimate pain.

This could mean that pain actually is more of an issue in those who were assisted by proxies.

The instruments used to assess HRQoL, pain, fatigue, physical activity etc. were not disease-specific and not disease-specifically tailored to individuals with childhood-onset disability. This introduces some likely degree of measurement error. This measurement error was likely non-systematic (apart from that stated about proxy responses above) and therefore probably resulted in some decreased accuracy. Habitual physical activity is difficult to evaluate in individuals in GMFCS levels IV-V and is overall probably better evaluated using wearable accelerometers (Clanchy et al., 2011) and perhaps wearable heart rate monitors.

The studies lacked data on bullying and ostracism. These are common burdens in individuals with disabilities (Holmberg, 2010; Twyman et al., 2010), including CP (Lindsay &

McPherson, 2012), which have negative effects on health status (Holmberg, 2010; Whitney et al., 2019). There is not much research done on bullying and social exclusion in CP and the effects they have on health and well-being. It is unfortunate that this was not included in the data collection as it has the potential to add additional clarity to the results and associations that were found. Future studies should incorporate these aspects.

4.3.2.1 External validity

The overall results should be generalizable to young adults about 21 years of age with CP living in societies with similar health-care systems and social support structures as in Sweden. Some findings, which are less environment-dependent, such as the association between less fatigue and more physical activity can probably be generalized even more broadly.

4.3.3 Paper III

The internal validity of the study should be considered adequate. The core outcome measure of gross motor function (GMFM-88) has largely been superseded by the GMFM-66 but it is still a valid and reliable gross motor measure. The use of the MAS to measure spasticity has its shortcomings (see Introduction section 1.3.1 and Methods section 3.5.7) but it remains the most widespread method, including most studies on SDR. A risk that has been reported is that the MAS has the potential to systematically misclassify contracture as spasticity when contractures are present (Patrick & Ada, 2006). Given that the MAS measurements were high preoperatively (before the development of contractures) and low at the long-term follow-up

(after contractures developed) means that any such misclassification, if present, had a minimal influence on study conclusions. For mobility, the Wilson Gait (Mobility) Scale has found little use in CP, where mobility more often is measured using the Function Mobility Scale (Graham et al., 2004). The FMS includes more options on wheeled mobility devices. It is possible that the results on mobility would have been different if the FMS was used.

The operations were performed with largely the same techniques as reported by other centers regarding intraoperative neurophysiology and percentage of rootlets cut.

Unfortunately, the follow-up did not include systematic radiography of the spine. Spinal complications are thus not systematically captured.

The Karolinska cohort of children whom had SDR had a similar distribution of GMFCS levels as the Lund cohort (Josenby et al., 2012) and the Vancouver cohort (Ailon et al., 2015) but more participants in GMFCS level IV compared to the Gillette cohort (Munger et al., 2017) and the Dutch cohort (Bolster et al., 2013), which has implications for the

interpretation of the development of gross motor function at the group level.

4.3.3.1 External validity

The inclusion and exclusion criteria are in line with those previously and currently practiced for SDR and the general results should be generalizable to children undergoing SDR at most centers where strict selection criteria are implemented. The SDR method produces a

significant and lasting reduction of spasticity without direct manipulation of the joint or muscle and therefore serves as a good experimental model for the study of spasticity reduction on contracture development. That contractures develop despite reduction or removal of spasticity, as measured using the MAS, can be generalized.

4.3.4 Paper IV

The paper can be argued to have good to excellent internal validity, mainly due to adherence to international consensus on methodology for randomized, placebo-controlled, double-blinded clinical trials. The blinding process was however not through delivery of coded vials from an external study pharmacy, which would be considered gold standard. At the time, in Stockholm, this turned out to be financially completely unfeasible. The process of blinding where the study nurse prepared coded syringes did however work well in that the blinding of the allocation remained intact with regards to both the treating team, the patient and the evaluating team.

From the perspective of the PRO’s, future studies should consider using PROMIS

measurements for added comparability with other studies, as well as longer registrations of baseline pain intensity and interference and perhaps pain follow-ups at shorter intervals using smartphone applications.

The main limitation of the study is however the small number of study participants; the sample size. This increases the risk of chance findings. It is however not definite that

forty-two participants would have made any major difference on the study conclusions compared to the present sixteen. This is because the primary outcome (proportion of responders at six weeks) was very likely to fail (probability of failure >80%) even if recruitment continued.

The interesting results and trends presented in paper IV are exploratory, i. e. found by chance, and not pre-specified. And these results would remain exploratory even with a larger sample.

The exploratory results would have less uncertainty, but they would still be exploratory. The conclusion from such a study (conducted with the same protocol but a larger sample) would be that there seems to be cause for trials of longer duration with the primary outcome later than six weeks after treatment. The author of this thesis would argue that we already have reached these very same conclusions, and this without exposing unnecessarily many human beings to experimental treatment.

4.3.4.1 External validity

As with most RCT’s, the generalizability of the results is restricted to those who conform to the strict inclusion and exclusion criteria (which are strict in order to maintain internal validity in the study). The results are generalizable to adults with spastic CP where the dominant pain mechanism is that of spasticity in the muscle: cramping, pulling, tenseness or other mechanical discomfort that can be linked to the presence and/or exacerbation of spasticity.