Perspective Biological Markers for Autism Spectrum Disorders: Advantages of the Use of Receiver Operating Characteristic Curves in Evaluating Marker Sensitivity and Specificity

Abstract

Autism Spectrum Disorders (ASD) are a heterogeneous group of neurodevelopmental disorders. Recognized causes of ASD include genetic factors, metabolic diseases, toxic and environmental factors, and a combination of these. Available tests fail to recognize genetic abnormalities in about 70% of ASD children, where diagnosis is solely based on behavioral signs and symptoms, which are difficult to evaluate in very young children. Although it is advisable that specific psychotherapeutic and pedagogic interventions are initiated as early as possible, early diagnosis is hampered by the lack of nongenetic specific biological markers. In the past ten years, the scientific literature has reported dozens of neurophysiological and biochemical alterations in ASD children; however no real biomarker has emerged. Such literature is here reviewed in the light of Receiver Operating Characteristic (ROC) analysis, a very valuable statistical tool, which evaluates the sensitivity and the specificity of biomarkers to be used in diagnostic decision making. We also apply ROC analysis to some of our previously published data and discuss the increased diagnostic value of combining more variables in one ROC curve analysis. We also discuss the use of biomarkers as a tool for advancing our understanding of nonsyndromic ASD.

Figure 1

Receiver Operating Characteristic (ROC) curve showing sensitivity as a function of 1 − specificity of erythrocyte Na⁺K⁺-ATPase activity in ASD and typically developing children. This is an example of a ROC curve obtained when the values of the two groups (autistic and typically developing children) do not overlap. When the AUC value is 1.00, the curve degenerates into a segment which lies parallel to the x-axis on top of the graph. The parameter of the figure was previously published by our group [56]. Values are shown in Table 7. ROC curve analysis was based on nonparametric methods. The confidence intervals of ROC curves were set at 95%.

Figure 2

Receiver Operating Characteristic (ROC) curves showing sensitivity as a function of specificity in ASD and typically developing (control) children. (a) Urinary 8-isoprostane, (b) urinary hexanoyl-lysine adduct; (c) erythrocyte membrane omega 6/omega 3; (d) total monounsaturated fatty acids of the erythrocyte membrane; (e) fluidity of erythrocyte membrane (inner leaflet); (f) thiobarbituric acid reactive substances in erythrocyte membranes; and (g) combined ROC curve of the six parameters. Some parameter values increase in autistic children with respect to typically developing ones, while others decrease. ROC curve analysis of a combination of multiple parameters, albeit with opposite sign, increases both sensitivity and specificity. Values of these parameters, reported in [56], are shown in Table 7. ROC curve analyses were based on nonparametric methods. The confidence intervals of ROC curves were set at 95%.