Abstract
Over the past 30 years, academic and industrial research investigators have developed molecular reporters to visualize cell death in complex biological systems. In parallel, clinical researchers, chemists, biochemists, and molecular biologists have endeavored to translate these molecular tools into clinical imaging agents. Despite these efforts, there are no clinically approved imaging methodologies with which to image cell death consistently and quantitatively. One reason may reside in the intrinsic mismatch between the sampling frequency of translational molecular imaging and the biochemical kinetics that define cell death. Beyond cell death imaging, many active research programs are now attempting to create translational diagnostic pharmaceuticals to image immunological, fibrotic, amyloidotic, and metabolic pathways. Each of these pathways is defined by a unique set of biochemical rate constants, some of which are associated with key predictive pathways. Exhaustively sampling all permutations of pathways and kinetic constants would seem to be an intractable strategy for target identification and validation. Sampling theory, if applied to these pathways, could accelerate the translation of high-impact diagnostics through prioritization of pathways for either AI enhanced diagnostic imaging or AI-enhanced wearable devices. In this perspective, we identify the Nyquist sampling rate as a key criterion for evaluating the optimal application for novel diagnostics. Sampling theory states that to fully characterize a band-limited, stationary, temporal data set, the signal must be sampled at more than twice the rate of the fastest frequency in the signal or, for diagnostics, the discriminatory signal. Through the study of the medical imaging process chain, Nyquist sampling rates of 0.25 day(-1) and, more likely, slower than 0.02 day(-1) were determined to provide high quality information. By prioritizing low-frequency predictive processes, or "state changes,", imaging researchers may improve the "hit rate" of research programs by appropriately matching the rate of change in diagnostic and predictive information with the limiting sampling rate of medical imaging. Critically, however, high-frequency diagnostic information (and therefore high-frequency biological processes) need not be ignored; these processes are simply better interrogated through continuous monitoring, e.g., by wearable devices combined with machine learning or artificial intelligence.