Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of design and analysis choices based on prespecified criteria, the Roadmap can help investigators to evaluate the quality of evidence that a given study is likely to produce, specify a study to generate high-quality RWE, and communicate effectively with regulatory agencies and other stakeholders. This paper aims to disseminate and extend the Causal Roadmap framework for use by clinical and translational researchers; three companion papers demonstrate applications of the Causal Roadmap for specific use cases.

Adoption of cover crops in arid agroecosystems has been slow due to concerns regarding limited water resources and possible soil moisture depletion. In irrigated organic systems, potential ecosystem services from cover crops also must be considered in light of the concerns for water conservation. A constructive balance could be achieved with fall-sown small grain cover crops; however, their impacts on irrigated organic systems are poorly understood. Our first objective was to determine the ability of fall-sown small grains [cereal rye (Secale cereale L), winter wheat (Triticum aestivum L.), barley (Hordeum vulgare L.) and oat (Avena sativa L.)] to suppress winter weeds in an irrigated, organic transition field in the southwestern USA. Small grains were planted following the legume sesbania (Sesbania exaltata (Raf.) Rydb. ex A.W. Hill) during Fall 2012 and Fall 2013. In Spring 2013 and 2014, weed densities and biomass were determined within each cover crop treatment and compared against unplanted controls. Results indicated that both barley and oat were effective in suppressing winter weeds. Our second objective was to compare weed suppression and soil moisture levels among seven barley varieties developed in the western United States. Barley varieties (‘Arivat’, ‘Hayes Beardless’, ‘P919’, ‘Robust’, ‘UC603’, ‘UC937’, ‘Washford Beardless’) were fall-sown in replicated strip plots in Fall 2016. Weed densities were measured in Spring 2017 and volumetric soil moisture near the soil surface (5.1 cm depth) was measured at time intervals beginning in December 2016 and ending in March 2017. With the exception of ‘UC937’, barley varieties caused marked reductions in weed density in comparison with the unplanted control. Soil moisture content for the unplanted control was consistently lower than soil moisture contents for barley plots. Barley variety did not influence volumetric soil moisture. During the 2017–2018 growing season, we re-examined three barley varieties considered most amenable to the cropping system requirements (‘Robust’, ‘UC603’, ‘P919’), and these varieties were again found to support few weeds (≤ 5.0 weeds m−2). We conclude that several organically certified barley varieties could fill the need for a ‘non-thirsty’ cover crop that suppresses winter weeds in irrigated organic systems in the southwestern United States.