Methods and systems for determining autism spectrum disorder risk

Abstract

In certain embodiments, the invention stems from the discovery that analysis of population distribution curves of metabolite levels in blood can be used to facilitate predicting risk of autism spectrum disorder (ASD) and/or to differentiate between ASD and non-ASD developmental delay (DD) in a subject. In certain aspects, information from assessment of the presence, absence, and/or direction (upper or lower) of a tail effect in a metabolite distribution curve is utilized to predict risk of ASD and/or to differentiate between ASD and DD.

What is claimed is: 
     
         1 . A method of differentiating between autism spectrum disorder (ASD) and non-ASD developmental delay (DD) in a subject, the method comprising:
 (i) measuring the levels of a plurality of metabolites in a sample obtained from the subject,   wherein the plurality of metabolites comprises at least two metabolites selected from the group consisting of xanthine, gamma-CEHC, hydroxy-chlorothalonil, 5-hydroxyindoleacetate (5-HIAA), indoleacetate, p-cresol sulfate, 1,5-anhydroglucitol (1,5-AG), 3-(3-hydroxyphenyl)propionate, 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), 3-indoxyl sulfate, 4-ethylphenyl sulfate, hydroxyisovaleroylcarnitine (C5), isovalerylglycine, lactate, N1-Methyl-2-pyridone-5-carboxamide, pantothenate (Vitamin B5), phenylacetylglutamine, pipecolate, 3-hydroxyhippurate, and combinations thereof; and   (ii) calculating the number of metabolites in the sample with a level at or below a predetermined threshold concentration:
 (a) indicative of ASD (ASD left tail effect) as defined in Table 9A, or 
 (b) indicative of DD (DD left tail effect) as defined in Table 9B; and/or 
   (iii) calculating the number of metabolites in the sample with a level at or above a predetermined threshold concentration:
 (a) indicative of ASD (ASD right tail effect) as defined in Table 9A, or 
 (b) indicative of DD (DD right tail effect) as defined in Table 9B; and 
   (iv) determining that the subject has ASD or DD based on the number obtained in steps (ii) and/or (iii).   
     
     
         2 . The method of  claim 1 , wherein the plurality of metabolites comprises xanthine and gamma-CEHC. 
     
     
         3 . The method of  claim 1 , wherein the sample is a plasma sample. 
     
     
         4 . The method of  claim 1 , wherein the metabolite levels are measured by mass spectrometry. 
     
     
         5 . The method of  claim 1 , wherein the subject is no greater than about 54 months of age. 
     
     
         6 . The method of  claim 1 , wherein the subject is no greater than about 36 months of age. 
     
     
         7 . A method for determining that a subject has or is at risk for ASD, the method comprising:
 (i) measuring the levels of a plurality of metabolites in a sample obtained from the subject,   wherein the plurality of metabolites comprises at least two metabolites selected from the group consisting of xanthine, gamma-CEHC, hydroxy-chlorothalonil, 5-hydroxyindoleacetate (5-HIAA), indoleacetate, p-cresol sulfate, 1,5-anhydroglucitol (1,5-AG), 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), 3-indoxyl sulfate, 4-ethylphenyl sulfate, hydroxyisovaleroylcarnitine (C5), isovalerylglycine, lactate, N1-Methyl-2-pyridone-5-carboxamide, pantothenate (Vitamin B5), phenylacetylglutamine, pipecolate, 3-hydroxyhippurate, and combinations thereof; and   (ii) detecting two or more of:
 (a) xanthine at a level of at or above 182.7 ng/ml; 
 (b) hydroxyl-chlorothalonil at a level at or above 20.3 ng/ml; 
 (c) 5-hydroxyindoleacetate at a level at or above 28.5 ng/ml; 
 (d) lactate at a level of at or above 686600.0 ng/ml; 
 (e) pantothenate at a level of at or above 63.3 ng/ml; 
 (f) pipecolate at a level at or above 303.6 ng/ml; 
 (g) gamma-CEHC at a level at or below 32.0 ng/ml; 
 (h) indoleacetate at a level at or below 141.4 ng/ml; 
 (i) p-cresol sulfate at a level at or below 182.7 ng/ml; 
 (j) 1,5-anhydroglucitol (1,5-AG) at a level at or below 11910.3 ng/ml; 
 (k) 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF) at a level at or below 7.98 ng/ml; 
 (l) 3-indoxylsulfate at a level at or below 256.7 ng/ml; 
 (m) 4-ethylphenyl sulfate at a level at or below 3.0 ng/ml; 
 (n) hydroxyisovaleroylcarnitine (C5) at a level at or below 12.9 ng/ml; 
 (o) N1-Methyl-2-pyridone-5-carboxamide at a level at or below 124.82 ng/ml; and 
 (p) phenacetylglutamine at a level at or below 166.4 ng/ml; and 
   (iii) determining that the subject has or is at risk for ASD based on the metabolite levels detected in step (ii).   
     
     
         8 . The method of  claim 7 , wherein the plurality of metabolites comprises xanthine and gamma-CEHC. 
     
     
         9 . The method of  claim 7 , wherein the sample is a plasma sample. 
     
     
         10 . The method of  claim 7 , wherein the metabolite levels are measured by mass spectrometry. 
     
     
         11 . The method of  claim 7 , wherein the subject is no greater than about 54 months of age. 
     
     
         12 . The method of  claim 7 , wherein the subject is no greater than about 36 months of age.