The influence of the probability density function on spectral quality in nonuniformly sampled multidimensional NMR.

The goal of nonuniform sampling (NUS) is to select a subset of free induction decays (FIDs) from the conventional, uniform grid in a manner that sufficiently samples short evolution times needed for improved sensitivity and long evolution times needed for enhanced resolution. In addition to specifying the number of FIDs to be collected from a uniform grid, NUS schemes also specify the distribution of the selected FIDs, which directly impacts sampling-induced artifacts. Sampling schemes typically address these heuristic guidelines by utilizing a probability density function (PDF) to bias the distribution of sampled evolution times. Given this common approach, schemes differentiate themselves by how the evolution times are distributed within the envelope of the PDF. Here, we employ maximum entropy reconstruction and utilize in situ receiver operating characteristic (IROC) to conduct a critical comparison of the sensitivity and resolution that can be achieved by three types of biased sampling schemes: exponential (PDF is exponentially decaying), Poisson-gap (PDF derived from a sine function), and quantile-directed (PDF defined by simple polynomial decay). This methodology reveals practical insights and trends regarding how the sampling schemes and bias can provide the highest sensitivity and resolution for two nonuniformly sampled dimensions in a three-dimensional biomolecular NMR experiment. The IROC analysis circumvents the limitations of common metrics when used with nonlinear spectral estimation (a characteristic of all methods used with NUS) by quantifying the spectral quality via synthetic signals that are added to the empirical dataset. Recovery of these synthetic signals provides a proxy for the quality of the empirical portion of the spectrum. The central finding is that differences in spectral quality are primarily driven by the strength of bias in the PDF. In addition, a sampling coverage threshold is observed that appears to be connected to the dependence of each NUS method on its random seed. The differences between sampling schemes and biases are most relevant below 20% coverage where seed-dependence is high, whereas at higher coverages, the performance metrics for all of the sampling schemes begin to converge and approach a seed-independent regime. The results presented here show that aggressive sampling at low coverage can produce high-quality spectra by employing a sampling scheme that adheres to a decaying PDF with a bias to a broad range of short evolution times and includes relatively few FIDs at long evolution times.