“…HRF estimation with a data-driven approach or a smoothness constraint has been previously explored. The adopted methods included various constraints through, for example, Gaussian process prior (Goutte et al, 2000; Ciuciu et al, 2003), cubic smoothing splines (Zhang et al, 2007) Tikhonov regularization (Zhang et al, 2007; Casanova et al, 2008; Casanova et al 2009; Zhang et al 2012), spatial regularization (Badillo et al, 2013; Chaari et al, 2013; Zhang et al, 2018), cross validation (Zhang et al, 2013), nonlinear optimization (Pedregosa et al, 2015). Some of these methods were limited to individual-level modeling (Goutte et al, 2000; Goutte et al, 2000; Ciuciu et al, 2003; Zhang et al, 2007; Chaari et al, 2013; Pedregosa et al, 2015), and their applicability, performance, and computational feasibility of these applications at the population level remain to be explored.…”