# Can the Discovery of High-Impact Diagnostics Be Improved by Matching the Sampling Rate of Clinical Diagnostics to the Frequency Domain of Diagnostic Information?

## TL;DR

The paper suggests using sampling theory to improve the development of diagnostics by matching the sampling rate to the biological processes being studied.

## Contribution

It introduces the use of Nyquist sampling rates to prioritize diagnostic targets based on their frequency domain characteristics.

## Key findings

- Low-frequency biological processes are better suited for medical imaging with sampling rates slower than 0.02 day−1.
- High-frequency processes should be monitored using wearable devices and AI for better interrogation.
- Matching sampling rates to biological process frequencies can improve diagnostic development efficiency.

## Abstract

Development of pure diagnostics, particularly injectable diagnostics, requires years of effort and a high cost to both the public and private sector. There is a nearly inexhaustible number of biochemical pathways or combinations of pathways that could be targeted to yield information on the disease state. Simultaneously, there is an explosion of wearable devices providing “continuous” readouts that are being coupled with machine learning and artificial intelligence (AI). Through the study of the time constants associated with medical imaging process chains, a method for prioritizing targets for either medical imaging or continuous device-mediated readout is proposed with the long-term goal of building high-value diagnostics to improve patient outcomes.

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.