The proposed method is based on an iterative estimation of the instantaneous curvature of the reference trajectory and coordinates transformation approach, and hence, it is effective for complex reference trajectories with high curvatures.
However, the once dominating paradigm of "mono drug mono target" in drug development is now being challenged by the clinical and pharmaceutical people, since the single drug cannot always be effective for the complex diseases (such as cancer and diabetes), which may involve multiple biological pathways and complex pathological process.
On the other hand, multi-drug therapies (MDT) have been proven to be effective for many complex diseases [ 10, 11].
In addition, group CBT was found to be effective for youth with complex comorbid conditions, including depression, attention deficit/hyperactivity disorder (ADHD) and pervasive developmental disorders (PDD) [ 12].
In addition, our approach also proves to be effective for three other complex detection algorithms proposed in recent years, i.e. CMC, COACH and RRW.
The wide variety of marking-associated genes (both regulatory and structural genes) identified by our screening indicates that a similar strategy will be effective for understanding other complex traits.
Although this q-value analysis was not perfect (e.g., we did not find a steady decrease of q-value by increasing gene score, Table 4), it suggests that multi-species gene ranking by optimal weighting matrix might be effective for prioritizing candidate genes for complex traits.
Metamodelling has been widely used in e.g. engineering, for speed-up of computations, sensitivity analysis and uncertainty assessment [ 37], and recently, multivariate metamodelling using PLSR [ 25- 28, 30, 38] and HC-PLSR [ 5, 6, 29] has been shown to be effective for analysis of the complex, nonlinear input output relationships of biological models.
We chose co-expression network analysis to uncover functional gene networks, as this approach has been shown to be effective for revealing molecular networks underlying complex disorders in human tissue samples [ 17– 20].
