Is Neonatale Screening op Mucoviscidose aangewezen in België?

12 Cystic Fibrosis Neonatal Screening KCE Reports 132
2.2.1.3 Methodological concerns about the 2 RCT studies
Cochrane reviewers identified six trials potentially fulfilling search criteria of RCT or
nearly-controlled randomized study about NBS outcomes but only two were retained
for further analyses of data based on strict eligibility and quality criteria of Cochrane’s
method selection. 42 The first RCT is the Wisconsin CF Neonatal Screening project
which randomly assigned 650 341 neonates born in Wisconsin during 1985-1994 to
either a screened (n = 325 171) or control group (n = 325 170). 53 The second RCT is
the UK trial where screening took place on alternate weeks from 1985 to 1989
55, 56
(screened group: n = 230 076, control group: n = 243 510).
From the latest published reports of these trials, Cochrane reviewers identified 108 CF
patients (57 in the screened group, 51 in the control group) and 176 CF patients (86 in
the screened group and 90 in the control group) respectively. 42 Risks of bias of these
studies were carefully analysed in this updated Cochrane review 42 and were most
critical for the UK trial where they included among others, a lack of consistency for an
intention-to-screen analysis and ascertainment bias (including a too heterogeneous
management in SG). The UK study finally was removed from the Cochrane analysis,
which left the Wisconsin study as unique RCT validated.
Some methodological remarks have to be made about the Wisconsin study too. First, to
avoid a risk of lead time bias in this RCT, only data after the unblinding of the control
group at four years of age were analysed and reported. 42 Thus, some important
comparative data before the age of 4 were considered not comparable and were thus
not evaluated by Cochrane reviewer as for example, the demographic data in both
groups at the time of diagnosis. 53
Another methodological issue- revealed by the unexpected high survival rate even in the
CG (no death prior to 10 years) - needs to be considered. The Wisconsin study was
not powered to evaluate mortality as an endpoint. 57, 58 However, the absence of death
before age 10 - unlike in the general paediatric population with CF in the respective
time period- is most probably secondary to the close follow-up provided in this RCT
which did not take place in the UK randomized trial. 58 Thus, although the results of that
RCT have internal validity, they may lacking external validity, which is not an uncommon
problem with RCTs. 58 The usual close monitoring of patients in RCT can lessen the
external validity or ‘generalizability’ of results to individuals receiving care in the
community. 57 In the Wisconsin study, several aspects of this unusually close monitoring
of infants and young children involved in this trial can be outlined. First, parents from
both groups were well informed about CF and NBS 54 and they knew that they could get
premature access to the assignment of their child if needed. It is remarkable that
(before unblinding) the median age at diagnosis in the CG was reduced by 13-14 weeks
compared to ‘usual’ time-to-clinical-based diagnosis in daily practice before start of the
trial (22-23 weeks instead of 36 weeks). 53 Moreover, the median age of diagnosis
continuously decreased along the randomization period. 50, 59, 60 This does not mean that
mothers brought numerous milder CF patients to clinical practice centre, but they
brought clinically suspected CF patients earlier than they would have done, if
uninformed about the disease.
Another ascertainment bias was generated by the interventions of the coordinators of
the study towards general practitioners (GP). GPs were regularly called and motivated
to detect as soon as possible any false-negative of NBS or any new CF cases from the
control group. 54
The Wisconsin Trial is however a landmark study and it should be realized that the
above described bias concordantly could have partially masked the benefits of CF NBS.
The same holds also true for the trend to higher proportion of pancreatic insufficient
patients and F508del homozygote in the screened group despite the randomization
process. 54 Even more importantly, the lack of consistent patient segregation in one of
the 2 led to a higher rate of Pseudomonas acquisition in the SG, again possibly masking
other possible screening advantages. The latter point has such prognostic implications
that it is further discussed elsewhere (2.3.2.6.1).