An electrophysiological biomarker for the classi ﬁ cation of cataract-reversal patients: A case-control study

Background: Untreated congenital blindness through cataracts leads to lasting visual brain system changes, including substantial alterations of extrastriate visual areas. Consequently, late-treated individuals ( > 5 months of age) with densecongenital bilateral cataracts (CC) exhibitpoorer visual function recovery compared to individ- uals with bilateral developmental cataracts (DC). Reliable methods to differentiate between patients with congenital and developmental cataracts are often lacking, impeding ef ﬁ cient rehabilitation management and introducing confounds in clinical and basic research on recovery prognosis and optimal timing of surgery. A persistent reduction of theP1 waveof visualevent-relatedpotentials(VERPs),associatedwithextrastriatevisualcor- tical activity, has been reportedin CC but not in DC individuals. Using two experiments, this study developed and validated P1-basedbiomarkers for diagnosing a history of congenital blindness in cataract-reversal individuals. Methods: Congenital and developmental cataract-reversal individuals as well as typically sighted matched controls took part in a ﬁ rst experiment used for exploring an electrophysiological biomarker ( N CC = 13, N DC = 13, N Control = 26). Circular stimuli containing gratings were presented in one of the visual ﬁ eld quadrants while visual event-related potentials (VERPs) were recorded. Two biomarkers were derived from the P1 wave of the VERP: (1) The mean of the normalized P1 amplitude at posterior electrodes, and (2) a classi ﬁ er obtained from a linear support vector machine (SVM). A second experiment with partially new CC/DC individuals and their matched controls ( N CC = 14, N DC = 15, N Control = 29) was consecutively used to validate the classi ﬁ cation based on both biomarkers. Performance of the classi ﬁ ers were evaluated using receiver operating characteristic (ROC) curve analyses. All cataract-reversal individuals were tested after at least one year of vision recovery. Findings: The normalized P1 amplitude over posterior electrodes allowed a successful classi ﬁ cation of the CC from the DC individuals and typically sighted controls (area under ROC curve, AUC = 0.803 and 0.929 for the normalized P1 amplitude and the SVM-based biomarker, respectively). The validation for both biomarkers in experiment 2 again resulted in a high classi ﬁ cation success (AUC = 0.800 and 0.883, respectively for the nor- malized P1 amplitude and the SVM-based biomarker). In the most conservative scenario involving classi ﬁ cation of CC from DC individuals in a group of only cataract-reversal individuals, excluding typically sighted controls, the SVM-based biomarker was found to be superior to the mean P1 amplitude based biomarker (AUC = 0.852 compared to 0.757 for the mean P1 based biomarker in validation). Minimum speci ﬁ city obtained was 80% across all biomarkers. Interpretation: A persistent reduction of the P1 wave provides a highly speci ﬁ c method for classifying cataract patients post-surgically as having suffered from bilateral congenital vs. bilateral developmental cataracts. We suggest that using the P1 based non-invasive electrophysiological biomarker will augment existing clinical classi ﬁ cation criteria for individuals with a history of bilateral congenital cataracts, aiding clinical and basic research, recovery prognosis, and rehabilitation efforts. Funding: (DFG) European Council (ERC).