Improving biosensor accuracy and speed using dynamic signal change and theory-guided deep learning.

False results and time delay are longstanding challenges in biosensing. While classification models and deep learning may provide new opportunities for improving biosensor performance, such as measurement confidence and speed, it remains a challenge to ensure that predictions are explainable and consistent with domain knowledge. Here, we show that consistency of deep learning classification model predictions with domain knowledge in biosensing can be achieved by cost function supervision and enables rapid and accurate biosensing using the biosensor dynamic response. The impact and utility of the methodology were validated by rapid and accurate quantification of microRNA (let-7a) across the nanomolar (nM) to femtomolar (fM) concentration range using the dynamic response of cantilever biosensors. Data augmentation and cost function supervision based on the consistency of model predictions and experimental observations with the theory of surface-based biosensors improved the F1 score, precision, and recall of a recurrent neural network (RNN) classifier by an average of 13.8%. The theory-guided RNN (TGRNN) classifier enabled quantification of target analyte concentration and false results with an average prediction accuracy, precision, and recall of 98.5% using the initial transient or entire dynamic response, which is indicative of high prediction accuracy and low probability of false-negative and false-positive results. Classification scores were used to establish new relationships among biosensor performance characteristics (e.g., measurement confidence) and design parameters (e.g., inputs and hyperparameters of classification models and data acquisition parameters) that may be used for characterizing biosensor performance.

Reduction of Biosensor False Responses and Time Delay Using Dynamic Response and Theory-Guided Machine Learning.

Here, we provide a new methodology for reducing false results and time delay of biosensors, which are barriers to industrial, healthcare, military, and consumer applications. We show that integrating machine learning with domain knowledge in biosensing can complement and improve the biosensor accuracy and speed relative to the performance achieved by traditional regression analysis of a standard curve based on the biosensor steady-state response. The methodology was validated by rapid and accurate quantification of microRNA across the nanomolar to femtomolar range using the dynamic response of cantilever biosensors. Theory-guided feature engineering improved the performance and efficiency of several classification models relative to the performance achieved using traditional feature engineering methods (TSFRESH). In addition to the entire dynamic response, the technique enabled rapid and accurate quantification of the target analyte concentration and false-positive and false-negative results using the initial transient response, thereby reducing the required data acquisition time (i.e., time delay). We show that model explainability can be achieved by combining theory-guided feature engineering and feature importance analysis. The performance of multiple classifiers using both TSFRESH- and theory-based features from the biosensor's initial transient response was similar to that achieved using the entire dynamic response with data augmentation. We also show that the methodology can guide design of experiments for high-performance biosensing applications, specifically, the selection of data acquisition parameters (e.g., time) based on potential application-dependent performance thresholds. This work provides an example of the opportunities for improving biosensor performance, such as reducing biosensor false results and time delay, using explainable machine learning models supervised by domain knowledge in biosensing.