Methods for disease treatment and drug discovery
Drug administration is performed in view of variation spatial profiling (VSP) of patients or potential patients. Spatial-covariance (SCV) relationships relate the position of the disease-associated variant in the polypeptide chain with cell-based models and clinical features of disease. An understanding of SCV relationships for a sparse collection of known fiduciary variants can be used to generate the shape of phenotype landscapes that measure the differential disease behavior for unknown variants, and between distinct cell and tissue environments in patients. The phenotype landscapes can determine which pharmaceutical compounds are administered to potential patients.
1 . A method of estimating a biological or chemical property of one or more molecule variants, wherein the molecule variants are characterized by different molecular features, the method comprising:
receiving or computing a first plurality of position values for a first plurality of molecular features;
receiving or computing a first plurality of severity values for a first phenotypic property exhibited by a cell or animal or patient harboring the molecule when the molecule contains each of the first plurality of molecular features;
receiving or computing a first plurality of severity values for a second phenotypic property different from the first phenotypic property exhibited by a cell or animal or patient harboring the molecule when the molecule contains each of the first plurality of molecular features;
computing a first plurality of two-dimensional coordinates, one for each of the first plurality of molecular features using the first plurality of position values of the first plurality of molecular features on a first coordinate axis and the first plurality of severity values of the first phenotypic property corresponding to each of the first plurality of molecular features on a second coordinate axis;
computing a distance in the plane defined by the first coordinate axis and the second coordinate axis between each different pair of the first plurality of computed two dimensional coordinates;
computing at least one relationship between the variance of the first plurality of severity values of the second phenotypic property and distance in the plane defined by the first coordinate axis and the second coordinate axis using sets of the computed distances that fall within defined distance ranges;
computing a second plurality of severity values for the second phenotypic property for a second plurality of two dimensional coordinates in the plane defined by the first coordinate axis and the second coordinate axis that are not among the first plurality of two dimensional coordinates of the first plurality of molecular features, wherein the computing of a severity value for the second phenotypic property for each given one of the second plurality of two dimensional coordinates is based at least in part on (1) the distance between the given one of the second plurality of two dimensional coordinates and each of the first plurality of two dimensional coordinates corresponding to the first plurality of molecular features, and (2) the severity value for the second phenotypic property at each of the first plurality of two dimensional coordinates corresponding to the first plurality of molecular features; and
generating a three-dimensional visualization of the computed severity values for the second phenotypic property at the second plurality of two-dimensional coordinates.
2 . The method of claim 1 , wherein the molecules are proteins, and the different molecular features are different amino acid sequence variants.
3 . The method of claim 1 , wherein the molecules are nucleic acids, and the different molecular features are different nucleotide sequence variants.
4 . The method of claim 1 , wherein the three-dimensional visualization associates different displayed colors with different severity levels for the second property.
5 . The method of claim 1 , additionally comprising computing confidence intervals for the estimated severity levels of the second property.
6 . The method of claim 1 , wherein the severity levels for the first property are normalized with respect to wild-type severity for the first property.
7 . The method of claim 2 , wherein the position values are normalized with respect to the length of the protein.
8 . The method of claim 1 , wherein the first phenotypic property is a first cellular level function associated with cells harboring molecules having each of the first plurality of molecular features.
9 . The method of claim 8 , wherein the second property is a second, different cellular level function associated with cells harboring molecules having each of the first plurality of molecular features.
10 . The method of claim 8 , wherein the second property is an organism level clinical property associated with an organism having cells harboring molecules having each of the first plurality of molecular features.