Table 1.

Biomarkers in development for autism spectrum disorder

Biomarker	Type (potential)	Period	Strength	Weakness	Validation studies
Prenatal history
Gestational infections	Risk	Prenatal	Can obtain from medical history	Not clear If specific to specific infection or if the effects of infection treatments (eg, antibiotics) have an effect. No clear treatment consequences other than standard of care	No
Obesity/diabetes	Risk	Prenatal	Can obtain from medical history	No clear treatment consequences other than standard of care	No
Genetics
Structural DNA alterations	Risk subgroup Treatment	All periods	High-throughput comprehensive genetic analysis is becoming clinically routine. Particularly helpful in difficult, refractory cases to provide prognostic information	Low yield for any single disorder and phenotype can be variable. Variants of unknown significance are common results leading to ambiguous information which can be hard to reconcile. Experienced geneticist is needed to interpret complex genetic information	No
Single nucleotide polymorphism	Risk Treatment	Postnatal	Single nucleotide polymorphism is generally available even on the consumer level	Lack of rigorous scientific research on risk association and treatment implications leads to dubious treatment recommendations based on results, especially at the consumer level	No
mRNA/miRNA	Diagnostic Subgroup	Post-diagnosis	Noninvasive. Some correlation with neurodevelopment outcomes	Variable performance in validation studies. Different RNA subtypes used in various studies. Utility unclear if diagnosis already established	Yes
Methylation	Risk Diagnostic	All periods	Biologically important. Important epigenetic factor than may explain inheritance and environmental exposures	Very variable results regarding direction of methylation abnormalities and specific gene target of methylations changes. Very complicated field given both inherited and environmental factors are at play	No
Neurological
Morphology and diffusion tensor imaging	Risk Diagnostic	Pre-diagnosis Post-diagnosis	Consistent abnormalities in brain growth appear prior to diagnosis and persist into the diagnostic period. Non-invasive	Large prospective studies are needed to validate findings. MRI may require specialized centers. Limited to infants and children that can tolerate MRI scanner	No
N170	Diagnostic	Post-Diagnosis	Non-invasive. No Sedation Needed	Requires cooperation and attention to view stimuli. Utility unclear if diagnosis already established. Large prospective studies are needed to validate findings	No
MEG	Diagnostic Treatment	Post-diagnosis	Non-invasive. No Sedation Needed. Possible association with GABA signaling leading to possible prediction of treatment response	Variable protocols limit conclusions from current research. Utility unclear if diagnosis already established. Large prospective studies are needed to validate findings	No
Resting state MRI	Risk Diagnostic	Pre-diagnosis Post-diagnosis	Non-invasive	Variable protocols limit conclusions from current research. Require specialized centers. Limited to infants and children that can tolerate MRI scanner	No
Visual attention	Risk Diagnostic	Pre-diagnosis Post-diagnosis	Non-invasive	Require specialized centers. Requires cooperation and attention to view stimuli	No
Metabolic
Transmethylation transsulphuration	Risk Diagnostic Treatment	All Periods	Only requires blood test. Possible prenatal predictive. Biologically important and possibly relevant to treatment	Requires specialized centers and equipment and not widely available clinically. May correlation with symptoms. Large prospective studies are needed to validate findings	Yes
Mitochondrial	Subgroup Treatment	Post-diagnosis	Various biomarkers, some non-invasive. Possibly biologically important and relevant to treatment	Variable techniques and biomarkers limit conclusions from current research. Large prospective studies using a validated biomarker are needed to validate findings	No
Immune
Maternal autism related (MAR)	Diagnostic	Prenatal	Possible prenatal prediction of ASD diagnosis with a high sensitivity for the MAR subgroup	Large prospective studies are needed to validate findings. Treatment implications unclear at this time	No
Brain autoantibodies	Treatment	Post-diagnosis	Possibly biologically important and relevant to treatment	Variable techniques and biomarkers limit conclusions from current research. Large prospective studies using a validated biomarker are needed to validate findings	No
Folate receptor alpha autoantibody	Risk Subgroup Treatment	All periods	Possible prenatal prediction of ASD diagnosis given that found also in parents May represent an ASD subgroup that is treatment responsive	May indicate distinct at-risk subgroup but lack sensitivity for ASD diagnosis. Transgenerational features require significant more investigation. Large prospective studies are needed to validate findings	No
Cytokines	Risk Subgroup Treatment	All periods	Elevated cytokines in pregnancy and neonatal period interesting as possible risk predictor. May indicate subgroup that requires specific treatment	Variable techniques and biomarkers limit conclusions from current research. Large prospective studies using a validated biomarker are needed to validate findings	No
Autonomic
Heart rate variability	Subgroup Treatment	Post-Diagnosis	May represent an ASD subgroup that is treatment responsive	Variable techniques and biomarkers limit conclusions from current research. Large prospective studies using a validated biomarker are needed to validate findings	No
Pupillometry	Diagnostic	Post-Diagnosis	Non-invasive	Variable techniques and biomarkers limit conclusions from current research	No
Zinc	Risk Subgroup	Prenatal Post-diagnosis	Abnormal zinc level in pregnancy period is an interesting possible risk predictor with treatment implications. May indicate subgroup that requires specific treatment	Deciduous teeth typically not available until after diagnosis so fetal zinc measurements would need to be developed. Treatment implications unclear	No
Vitamin D	Risk Treatment	Prenatal Post-diagnosis	Easily obtained prenatally with routine laboratories and treatment implications straightforward. Biologically relevant	Target optimum vitamin D level widely debated. Large prospective studies are needed to validate findings	No
Folate	Risk	Pre-diagnosis	Easily obtained with routine laboratories	The complicated nature of various folate species is not captured in routine total folate levels and the interaction with other folate pathway abnormalities makes routine levels hard to interpret on their own	No

ASD autism spectrum disorder, DNA deoxyribonucleic acid, GABA gamma-aminobutyric acid, MRI magnetic resonance imaging, MAR maternal autism related, mRNA messenger RNA, miRNA microRNA, RNA ribonucleic acid