Increasing data rates and reduced design margins oppose a detailed consideration of the diverse aspects of high-speed digital links, such as the passive channel, equalization, and coding. This work offers novel methods for the computationally efficient design and validation of links. A combined system perspective is established based on predominant physical parameters of the interconnect and key parameters of equalizer design. This enables a systematic prediction of design constraints and is accompanied by a study of advanced uncertainty quantification methods for pre- and post-layout design.