Improved unsupervised physics-informed deep learning for intravoxel-incoherent motion modeling and evaluation in pancreatic cancer patients

${\bf Purpose}$: Earlier work showed that IVIM-NET$_{orig}$, an unsupervised physics-informed deep neural network, was faster and more accurate than other state-of-the-art intravoxel-incoherent motion (IVIM) fitting approaches to DWI. This study presents: IVIM-NET$_{optim}$, overcoming IVIM-NET$_{orig}$'s shortcomings. ${\bf Method}$: In simulations (SNR=20), the accuracy, independence and consistency of IVIM-NET were evaluated for combinations of hyperparameters (fit S0, constraints, network architecture, # hidden layers, dropout, batch normalization, learning rate), by calculating the NRMSE, Spearman's $\rho$, and the coefficient of variation (CV$_{NET}$), respectively. The best performing network, IVIM-NET$_{optim}$ was compared to least squares (LS) and a Bayesian approach at different SNRs. IVIM-NET$_{optim}$'s performance was evaluated in 23 pancreatic ductal adenocarcinoma (PDAC) patients. 14 of the patients received no treatment between 2 repeated scan sessions and 9 received chemoradiotherapy between sessions. Intersession within-subject standard deviations (wSD) and treatment-induced changes were assessed. ${\bf Results}$: In simulations, IVIM-NET$_{optim}$ outperformed IVIM-NET$_{orig}$ in accuracy (NRMSE(D)=0.14 vs 0.17; NMRSE(f)=0.26 vs 0.31; NMRSE(D*)=0.46 vs 0.49), independence ($\rho$(D*,f)=0.32 vs 0.95) and consistency (CV$_{NET}$ (D)=0.028 vs 0.185; CV$_{NET}$ (f)=0.025 vs 0.078; CV$_{NET}$ (D*)=0.075 vs 0.144). IVIM-NET$_{optim}$ showed superior performance to the LS and Bayesian approaches at SNRs<50. In vivo, IVIM-NET$_{optim}$ showed less noisy and more detailed parameter maps with lower wSD for D and f than the alternatives. In the treated cohort, IVIM-NET$_{optim}$ detected the most individual patients with significant parameter changes compared to day-to-day variations. ${\bf Conclusion}$: IVIM-NET$_{optim}$ is recommended for accurate IVIM fitting to DWI data.