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The present study evaluates the water quality status of 6-km-long Kali River stretch that passes through the Aligarh district in Uttar Pradesh, India, by utilizing high-resolution IRS P6 LISS IV imagery. In situ river water samples collected at 40 random locations were analyzed for seven physicochemical and four heavy metal concentrations, and the water quality index (WQI) was computed for each sampling location. A set of 11 spectral reflectance band combinations were formulated to identify the most significant band combination that is related to the observed WQI at each sampling location. Three approaches, namely multiple linear regression (MLR), backpropagation neural network (BPNN) and gene expression programming (GEP), were employed to relate WQI as a function of most significant band combination. Comparative assessment among the three utilized approaches was performed via quantitative indicators such as R2, RMSE and MAE. Results revealed that WQI estimates ranged between 203.7 and 262.33 and rated as "very poor" status. Results further indicated that GEP performed better than BPNN and MLR approaches and predicted WQI estimates with high R2 values (i.e., 0.94 for calibration and 0.91 for validation data), low RMSE and MAE values (i.e., 2.49 and 2.16 for calibration and 4.45 and 3.53 for validation data). Moreover, both GEP and BPNN depicted superiority over MLR approach that yielded WQI with R2 ~ 0.81 and 0.67 for calibration and validation data, respectively. WQI maps generated from the three approaches corroborate the existing pollution levels along the river stretch. In order to examine the significant differences among WQI estimates from the three approaches, one-way ANOVA test was performed, and the results in terms of F-statistic (F = 0.01) and p-value (p = 0.994 > 0.05) revealed WQI estimates as "not significant," reasoned to the small water sample size (i.e., N = 40). The study therefore recommends GEP as more rational and a better alternative for precise water quality monitoring of surface water bodies by producing simplified mathematical expressions. [ABSTRACT FROM AUTHOR]