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We develop and evaluate a new method for estimating and optimizing various performance metrics of multi-hop wireless networks, including MANETs. We introduce a simple approximate (throughput) loss model that couples the physical, MAC and routing layers effects. The model provides quantitative statistical relations between the loss parameters that are used to characterize multiuser interference and physical path conditions on the one hand and the traffic rates between origin-destination pairs on the other. The model considers effects of the hidden nodes, node scheduling algorithms, MAC and PHY layer failures and unsuccessful packet transmission attempts at the MAC layer in arbitrary network topologies where multiple paths share nodes. We apply automatic differentiation (AD) to these implicit performance models, and develop a methodology for sensitivity analysis and parameter optimization for wireless protocols. Finally, we provide simulation experiments to evaluate the effectiveness and performance estimation accuracy of the proposed models and methodologies.