TABLE 4.

Should ketogenic therapies compared with control be used for people with Parkinson's disease or MCI secondary to Parkinson's disease?

GRADE domain	Judgement	Concerns about certainty domains
Methodological limitation of the studies	Both of the included studies in PD were judged to be at high risk of bias overall (56, 60). Although both studies reported on allocation concealment, there was no information available on random sequence generation, which lowered our certainty in the evidence. Further, in both studies participants and those delivering the intervention were aware of the participant's assigned intervention group. Therefore, we have judged the trials to have very serious methodological limitations	Very serious
Indirectness	The participants, interventions, and comparators all provide direct evidence to the clinical question. Both studies used a dietary intervention to induce ketosis and included participants with PD, however, 1 study specifically assessed participants with MCI secondary to PD (60). As such, different clinical outcomes were measured between trials. Krikorian used neuropsychological testing to evaluate cognitive changes (60), whilst Phillips measured motor function and activities of daily living using the MDS-UPDRS-I-IV (56). Krikorian also employed the MDS-UPDRS-I-IV to measure motor function, however, this was a secondary outcome in the study. We judged the evidence to have no serious indirectness	Not serious
Imprecision	The total number of participants across both trials was 61, which was concerning. Both trials reported mixed results in outcome measures assessed with significant and nonsignificant effects observed (56, 60). Due to the small sample size the precision and reliability of presented trials is low. We judged the evidence to be at very serious risk of imprecision	Very serious
Inconsistency	As primary outcome measures differed across studies, it was not possible to compare the consistency of magnitude of effects in included studies. Hence, we judged the evidence to be at very serious risk of inconsistency	Very serious
Publication bias	We did not suspect publication bias, due to the presence of both positive and negative trials in the evidence base. Furthermore, the systematic search strategy was comprehensive and covered an extensive number of databases	Not suspected

GRADE, Grading of Recommendations, Assessment, Development and Evaluation; MCI, mild cognitive impairment; MDS-UPDRS I-IV, Movement Disorders Society-Unified Parkinson Disease Rating Scale Parts I-IV; PD, Parkinson's disease.