Publications

  • Goldenholz, Daniel M, Shira R Goldenholz, Rohan Bhansali, Ted J Kaptchuk, and Brandon Westover. (2026) 2026. “Device Sensitivity and False Alarms Can Reshape Regression-to-the-Mean in Simulated Epilepsy Trials.”. MedRxiv : The Preprint Server for Health Sciences. https://doi.org/10.64898/2026.07.30.26359361.

    UNLABELLED: Automated seizure detection devices are increasingly plausible tools for epilepsy trials, but no device is perfect. We used CHOCOLATES, a realistic seizure diary simulator, to examine how device sensitivity and false alarm rate (FAR) affect regression-to-the-mean (RTM) and placebo median percentage change (MPC) in a simulated randomized trial design. For each device condition, 100,000 potential participants were generated; eligibility was assessed during a 2-month baseline, followed by a 3-month test period. With FAR fixed at 0, reducing sensitivity from 100% to 10% increased the fraction of eligible participants exhibiting RTM from 38.2% to 64.8% and increased placebo MPC from 14.7% to 48.1%. With sensitivity fixed at 100% and expected FAR correction, increasing FAR from 0 to 1 alarm/day increased RTM from 38.2% to 53.2% and placebo MPC from 14.7% to 31.3%. Imperfect seizure detection can therefore change the apparent placebo response expected from RTM.

    SHORT SUMMARY FOR TABLE OF CONTENTS: In simulated epilepsy trials, imperfect seizure detection altered regression to the mean and placebo median percentage change. Trial planning should model detector sensitivity and false alarm rate before device-derived seizure counts are used as endpoints.

  • Goldenholz, Daniel M, Rohan Bhansali, Ted J Kaptchuk, and Brandon Westover. (2026) 2026. “The Anatomy of Regression-to-the-Mean in Simulated Epilepsy Trials.”. MedRxiv : The Preprint Server for Health Sciences. https://doi.org/10.64898/2026.07.27.26359051.

    Regression to the mean (RTM) can inflate apparent placebo response in epilepsy trials, but its mechanisms are often conflated. Using CHOCOLATES, we simulated 1,000,000 patients with 36 months of daily seizure counts and simulated placebo trials: 2-month baselines followed by 3-month test periods without treatment effects. Transient worsening (RTM type 1), stricter eligibility thresholds (RTM type 2), reduced sensitivity, and false alarms (RTM type 3) each increased RTM and apparent response. These findings show that placebo-arm improvement can arise from temporary illness, natural variability, measurement error, or mixtures thereof, informing epilepsy trial design and endpoint interpretation.

  • Karoly, Philippa J, Rachel E Stirling, Mark J Cook, Daniel M Goldenholz, Maxime O Baud, Vikram R Rao, Solveig Vieluf, and Benjamin H Brinkmann. (2026) 2026. “Seizure Forecasting: The Long and Winding Road to Clinical Translation.”. Epilepsia. https://doi.org/10.1002/epi.70394.

    Seizure forecasting has progressed from theoretical aspiration to a rapidly advancing research domain, yet clinical translation remains limited. Over the past decades, advances in algorithm development, chronic electroencephalography (EEG), wearable sensors, and the characterization of seizure cycles have demonstrated that seizure risk is not random but fluctuates according to identifiable biological rhythms and patient-specific patterns. Forecasting algorithms have shown promising performance across diverse retrospective datasets, including intracranial EEG, subscalp recordings, wearable physiological signals, and even self-reported diaries. However, the clinical value of forecasting is contentious. Prospective real-world validation and regulatory approval of patient-facing forecasting systems remain rare. This review incorporates perspectives presented at the 5th International Congress on Mobile Health and Digital Technology in Epilepsy (2025). We examine barriers impeding clinical translation and current attempts to address them. Crucially, forecasting performance cannot be evaluated in isolation from intended use. Applications range from low-risk uses, like scheduling diagnostic monitoring or visualization of historical trends, to higher risk interventions, including medication titration and adaptive neuromodulation. Each application entails distinct performance thresholds, ethical considerations, and regulatory requirements. Translational challenges include reliable seizure annotation, nonstationarity dynamics of biological cycles, and practical constraints for real-time deployment. Ethical concerns center on miscalibrated reliance on low-risk states, potential anxiety associated with high-risk advisories, and the heterogeneity of patient preferences and risk tolerance. Regulatory pathways are likely to depend on clearly defined use cases and clinically meaningful endpoints, which may extend beyond seizure counts to include quality of life, anxiety, locus of control, and other patient-reported outcomes. Ultimately, translation will require rigorous prospective evaluation against transparent benchmarks, sustainable scientific-commercial partnerships, and integration of probabilistic risk information into clinical workflows. With careful implementation, seizure forecasting may evolve from proof-of-concept research into a clinically meaningful component of epilepsy management, and we remain cautiously optimistic.