Background In biomedicine, machine learning (ML) has proven beneficial for the prognosis and diagnosis of dif‑ferent diseases, including cancer and neurodegenerative disorders. For rare diseases,... Show moreBackground In biomedicine, machine learning (ML) has proven beneficial for the prognosis and diagnosis of dif‑ferent diseases, including cancer and neurodegenerative disorders. For rare diseases, however, the requirementfor large datasets often prevents this approach. Huntington’s disease (HD) is a rare neurodegenerative disorder causedby a CAG repeat expansion in the coding region of the huntingtin gene. The world’s largest observational studyfor HD, Enroll‑HD, describes over 21,000 participants. As such, Enroll‑HD is amenable to ML methods. In this study, wepre‑processed and imputed Enroll‑HD with ML methods to maximise the inclusion of participants and variables. Withthis dataset we developed models to improve the prediction of the age at onset (AAO) and compared it to the well‑established Langbehn formula. In addition, we used recurrent neural networks (RNNs) to demonstrate the utility of MLmethods for longitudinal datasets, assessing driving capabilities by learning from previous participant assessments.Results Simple pre‑processing imputed around 42% of missing values in Enroll‑HD. Also, 167 variables were retainedas a result of imputing with ML. We found that multiple ML models were able to outperform the Langbehn formula.The best ML model (light gradient boosting machine) improved the prognosis of AAO compared to the Langbehnformula by 9.2%, based on root mean squared error in the test set. In addition, our ML model provides more accu‑rate prognosis for a wider CAG repeat range compared to the Langbehn formula. Driving capability was predictedwith an accuracy of 85.2%. The resulting pre‑processing workflow and code to train the ML models are available to beused for related HD predictions at: https:// github. com/ Jaspe rO98/ hdml/ tree/ main.Conclusions Our pre‑processing workflow made it possible to resolve the missing values and include most par‑ticipants and variables in Enroll‑HD. We show the added value of a ML approach, which improved AAO predictionsand allowed for the development of an advisory model that can assist clinicians and participants in estimating futuredriving capability. Show less
Bakels, H.S.; Feleus, S.; Dis, V. van; Bot, S.T. de 2022
Huntington's Disease (HD) is a rare, neurodegenerative disorder characterized by chorea, cognitive decline, and behavioral changes. Despite wide clinical use since the mid-1980s, tiapride was... Show moreHuntington's Disease (HD) is a rare, neurodegenerative disorder characterized by chorea, cognitive decline, and behavioral changes. Despite wide clinical use since the mid-1980s, tiapride was recently withdrawn from the Dutch market without rationale. Although alternatives are available, many patients experienced dysregulation after this unwanted change. We provide insight into the impact of sudden tiapride withdrawal by reviewing medical records of HD patients who were using tiapride at the time of withdrawal. In addition, we performed a systematic search in five databases on tiapride efficacy and its safety profile in HD. Original research and expert opinions were included. In our patient group on tiapride, 50% required tiapride import from abroad. Regarding the review, 12 articles on original datasets and three expert opinions were included. The majority of studies showed an improvement in chorea while patients were on tiapride. Due to limited sample sizes, not all studies performed statistical tests on their results. Fifty percent of clinical experts prefer tiapride as initial chorea monotherapy, especially when comorbid behavioral symptoms are present. Side effects are often rare and mild. No safety concerns were reported. In conclusion, tiapride is almost irreplaceable for some patients and is an effective and safe chorea treatment in HD. Show less
Feleus, S.; Schaijk, M. van; Roos, R.A.C.; Bot, S. de 2021
Background Chorea is a distinct feature of Huntington{\textquoteright}s Disease (HD) and can be treated with various drugs. Although (deu)tetrabenazine is the only drug endorsed for chorea control... Show moreBackground Chorea is a distinct feature of Huntington{\textquoteright}s Disease (HD) and can be treated with various drugs. Although (deu)tetrabenazine is the only drug endorsed for chorea control by an RCT, it is not suitable for every HD patient due to its side effect profile. (Deu)tetrabenazine is contraindicated in patients with severe depression and/or previous suicidal thoughts. Antipsychotics are then used as off-label alternatives. In Northern Europe, tiapride is therefore regularly prescribed and also highly affordable with {\texteuro}0.55/day for 200 mg. However, tiapride was recently taken off-market in the Netherlands without rationale. As we have very good experiences with tiapride for HD chorea treatment, we decided to evaluate tiapride by performing a systematic review.Aims To review the efficacy and safety profile of tiapride in HD.Methods A systematic search in PubMed, Web of Science, PsychInfo, Embase and the Cochrane Library was performed. Original research on the efficacy or safety profile of tiapride and expert opinions regarding prescribing preferences to treat chorea were included. Tiapride{\textquoteright}s drug safety profile was additionally examined via national and international databanks.Results 11 original data articles and 3 expert opinions were included. The majority of studies (7 out of 11) showed an improvement in chorea while on tiapride. No significant worsening of chorea under tiapride was observed. Due to limited sample sizes not all studies performed statistical tests on their results. In the EU, up to 50\% of HD experts prefer tiapride as first choice monotherapy to treat chorea. Antipsychotics are unanimously favored to treat chorea when comorbid behavioural symptoms are present. Tiapride is generally well tolerated without major safety concerns. Side effects, such as drowsiness, elevated prolactin levels and fatigue, are often rare (< 10\%) and mild.Conclusions Tiapride can be an effective and safe alternative to tetrabenazine while treating chorea in HD. Show less
Background and purpose Subthalamic deep brain stimulation (STN DBS) is an effective therapy against medication-refractory motor complications in patients with Parkinson's disease. However, it... Show moreBackground and purpose Subthalamic deep brain stimulation (STN DBS) is an effective therapy against medication-refractory motor complications in patients with Parkinson's disease. However, it remains difficult to predict which baseline patient characteristics are associated with quality of life (QoL) after surgery. The objective was to identify preoperative factors associated with QoL after STN DBS by systematically reviewing publications of sufficient methodological quality. Methods Main databases were systematically searched up to March 2019 to identify studies that investigated factors associated with QoL after STN DBS in patients with idiopathic Parkinson's disease. Results In all, 869 studies were identified, of which 18 fulfilled the inclusion criteria. Higher QoL after DBS appears to be associated with a large preoperative difference between ON and OFF motor function in some studies, although there was no clear association of severity of motor function or motor complications with postoperative QoL. Lower severity of dyskinesias was associated with greater postoperative QoL improvement but has been insufficiently studied. Higher baseline QoL was suggestive of higher postoperative QoL. Four studies suggested that older age at surgery is associated with a lower improvement, although six other studies reported no association. No or limited evidence was found for cognitive impairment or psychiatric dysfunction. Conclusion Various relative contraindications for STN DBS such as cognitive impairment and psychiatric dysfunction appear to be unrelated to postoperative QoL. However, the lack of clear correlations with disease-related variables suggests that QoL may be individually influenced by other factors, indicating that an ideal preoperative patient profile with regard to QoL improvement cannot be readily provided. Show less
