An Exploratory Study of Blood Glucose Estimation from Photoplethysmography Signals using Machine Learning

Non-invasive blood glucose level (BGL) estimation from photoplethysmography (PPG) holds great promise for wearable health monitoring, but results across studies are hard to compare due to inconsistent datasets, data leakage, and non-standardized evaluation metrics. We present the first reproducible, extensible evaluation pipeline and use it to reassess five representative PPG-based BGL methods on published datasets under three increasingly strict data-split protocols: random window-level, participant-aware, and leave-some-participants-out (LSPO). Models appeared competitive under random splitting but collapsed under participant-aware and LSPO evaluation, with nearly all yielding near-zero or negative R$^2$ values comparable to a mean-prediction baseline. Critically, across every model and split, over 90% of predictions fell within clinically acceptable zones (Clarke Error Grid A+B), including the baseline. This reveals a fundamental disconnect: clinical zone metrics systematically conceal model failure in this domain. Our findings demonstrate that random train-test splits substantially overestimate the generalization of PPG-based BGL models due to sample-level data leakage, and that robust ML evaluation must precede clinical validation to meaningfully assess real-world utility.

Continuous cuffless blood pressure (BP) monitoring is essential for connected health systems and wearable devices, enabling early detection, longitudinal tracking, and personalized management of cardiovascular disease. Many prior approaches attempt to estimate BP indirectly by reconstructing electrocardiography (ECG) from photoplethysmography (PPG), assuming ECG provides a stronger physiological link to BP. However, ECG sensing is less accessible in wearable settings and may introduce unnecessary complexity. In this work, we first perform a large-scale physiological correlation analysis on the MIMIC-III waveform database, revealing that PPG exhibits substantially stronger coupling with arterial blood pressure (ABP) ($|r|=0.247$, $p<0.001$) than ECG does ($r=0.018$, $p=0.187$), challenging the assumption that ECG provides a superior intermediate representation. Motivated by this insight, we conduct a systematic comparison between direct PPG-to-BP prediction and ECG-mediated pipelines using multiple state-of-the-art deep learning models. Across 1.74M segments from 3,127 patients, direct PPG-to-BP prediction achieves British Hypertension Society Grade A performance ($\mathrm{MAE}_{\mathrm{SBP}} = 4.82 mmHg$, $\mathrm{MAE}_{\mathrm{DBP}} = 4.31 mmHg$), outperforming all ECG-mediated approaches, which achieve only Grade B accuracy. Our findings suggest that accurate continuous BP monitoring can be achieved directly from wearable PPG signals, enabling simpler, more efficient pipelines for real-world connected health systems.

Accurate blood glucose forecasting using continuous glucose monitoring (CGM) data can support the early prediction of dysglycemic risk. However, current neural-network-based forecasting models treat CGM data as a purely numerical sequence without integrating the contextual information contained in CGM signal morphology. Recently, large language models (LLMs) have shown promise for time-series forecasting, yet their role as agentic context extractors in diabetes care remains largely unexplored. In this study, we bridge glucose forecasting and LLM-based contextualization by developing GlyRAG, a context-aware, retrieval-augmented forecasting framework that uses an LLM as a contextualization agent to summarize glucose morphology directly from a timed CGM window. The generated CGM-only narrative is embedded and fused with patch-based glucose representations, while a retrieval module incorporates similar historical training episodes through cross-attention. We evaluate GlyRAG on the OhioT1DM and AZT1D datasets for 5-, 30-, and 60-minute forecasting horizons. Compared with strong CGM-only baselines, GPT-4 GlyRAG significantly improves long-horizon root mean square error (RMSE) over PatchTST on both datasets. For example, RMSE decreases from 13.8 to 10.6 at 30 minutes and from 23.1 to 20.2 at 60 minutes on OhioT1DM. LLaMA 3.1 produces smaller but significant long-horizon gains, suggesting that the contextualization pipeline is not limited to GPT-4. Clinical error-grid analyses further show that approximately 85 percent of predictions fall within the clinically acceptable Clarke Error Grid Zones A and B. These results suggest that CGM-derived linguistic context and case-based retrieval can improve long-horizon glucose forecasting without requiring additional sensing modalities.