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.

1 - 29 . (canceled) 
     
     
         30 . A method comprising steps of:
 (i) obtaining a first set of blood samples from human subjects having autism spectrum disorder (ASD) and a second set of blood samples from human subjects having non-ASD developmental delay (DD);   (ii) measuring levels of metabolites in the first and second set of samples,   wherein the metabolites comprise 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, 8-hydroxyoctanoate, hydroxyisovaleroylcarnitine (C5), isovalerylglycine, lactate, N1-Methyl-2-pyridone-5-carboxamide, pantothenate (Vitamin B5), phenylacetylglutamine, pipecolate, 3-hydroxyhippurate, and octenoylcarnitine;   (iii) determining a distribution profile for the metabolites in the first set and second set of samples, wherein the distribution profile has a lower end and an upper end;   (iv) defining for each metabolite:
 (a) a first threshold at the lower end of the distribution profile (left tail), wherein the first threshold is the 15 th  percentile; and 
 (b) a second threshold at the upper end of the distribution profile (right tail), wherein the second threshold is the 90 th  percentile. 
   
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 30 , wherein the blood samples is are plasma samples. 
     
     
         33 . The method of  claim 30 , wherein the metabolite levels are measured by mass spectrometry. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . A method of differentiating between autism spectrum disorder (ASD) and non-ASD developmental delay (DD) in a human subject, the method comprising steps of:
 (i) measuring the levels of a plurality of metabolites in a blood 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, 8-hydroxyoctanoate, hydroxyisovaleroylcarnitine (C5), isovalerylglycine, lactate, N1-Methyl-2-pyridone-5-carboxamide, pantothenate (Vitamin B5), phenylacetylglutamine, pipecolate, 3-hydroxyhippurate, and octenoylcarnitine;   (ii) calculating the number of metabolites measured in step (i) selected from 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF), 3-indoxyl sulfate, 4-ethylphenyl sulfate, 8-hydroxyoctanoate, gamma-CEHC, hydroxyisovaleroylcarnitine (C5), indoleacetate, isovalerylglycine, N1-Methyl-2-pyridone-5-carboxamide, p-cresol sulfate, phenylacetylglutamine, octenoylcarnitine, and 1,5-anhydroglucitol (1,5-AG) with a level in the sample at or below the lower threshold as defined in step (iv) of  claim 30  (ASD left tail);   (iii) calculating the number of metabolites measured in step (i) selected from 5-hydroxyindoleacetate, lactate, pantothenate (Vitamin B5), pipecolate, xanthine, and hydroxy-chlorothalonil with a level in the sample at or above the upper threshold as defined in step (iv) of  claim 30  (ASD right tail);   wherein a higher number of metabolites calculated in (ii) and (iii) is indicative of a higher likelihood that a subject has ASD;   (iv) calculating the number of metabolites measured in step (i) selected from 3-(3-hydroxyphenyl)propionate, pipecolate, xanthine, and 3-hydroxyhippurate with a level in the sample at or below the lower threshold as defined in step (iv) of  claim 30  (DD left tail);   (v) calculating the number of metabolites measured in step (i) selected from 3-indoxyl sulfate, isovalerylglycine, p-cresol sulfate, and phenylacetylglutamine with a level in the sample at or above the upper threshold as defined in step (iv) of  claim 30  (DD right tail);   wherein a higher number of metabolites calculated in (iv) and (v) is indicative of a higher likelihood that a subject has DD; and   (vi) determining that the subject has ASD or DD based on the number obtained in steps (ii)-(iii) and/or (iv)-(v).   
     
     
         37 . The method of  claim 36 , wherein the blood sample is a plasma sample. 
     
     
         38 . The method of  claim 36 , wherein the metabolites are measured by mass spectrometry. 
     
     
         39 . The method of  claim 36 , wherein the subject is no greater than about 54 months of age. 
     
     
         40 . The method of  claim 36 , wherein the subject is no greater than about 36 months of age.