The first and third challenges mentioned above, those of the genetic 'dark matter' and allele causality (coupled to mutational models), are more complex and are probably interlinked.
Directionality of cortical information-flow was calculated based upon an established Granger-Causality coupling-measure (partial-directed coherence; PDC) using autoregressive modeling.
Its cross sectional design, coupled with a non-random facility selection, limits any tests for causality.
Gene-editing approaches using CRISPRs or TALENs coupled with expression studies and/or proteomics can be used to not only establish causality of disease-causing mutations, but also to validate the effect of genetic modifiers.
The methodologies to test any coupled relationship to pairs of district gene expressions are based on (1) Granger causality, (2) correlation-basis approach, and (3) Glass-s-d score as defined in [ 60].
For example, consider a case of three-neurons in which neuron X is coupled via a synapse to a mediating neuron, Y, who is then connected to a third neuron, Z, illustrated in panel (a) of Figure 2. A Granger causality analysis between each pair would correctly identify the relationship between X and Y, and Y to Z.
Fig. (1Di) and (1Ei) show that the normal Granger AR method can only detect the causality spectra at the intrinsic coupling frequency around 34 Hz, but the Harmonic method is capable of detecting the causal influence at the external driving frequency at 10 Hz.
This circular causality is a necessary aspect of coupling variables that fluctuate over separable timescales.
It is important to note that we cannot draw conclusion about the causality between absence of γ-γ coupling from lPM to SMA and impaired motor function.
Because this first analysis involved a risk of reversed causality, the second analysis was run excluding couples who divorced within 4 years after baseline, reducing the sample to 19,511 couples.
Partial Directed Coherence is a statistical measure that is related to the concept of Granger Causality [ 46] and is able to detect asymmetric coupling between the compared voxels for a given frequency range.
