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The natural course of any disease can be described as progression from the first occurrence of disease to the first episode of symptoms, which may lead to a primary care consultation and subsequent treatment. For some conditions patients will be referred to secondary care. The population available to the researcher at each of these stages differs in terms of severity of symptoms, stage of disease, patient attitudes, and response to treatment. Research undertaken in secondary care is subject to biases of case selection and referral and may underestimate the prevalence of disease and overestimate the impact on quality of life compared with observations in primary care. Interventions shown to be effective in secondary care may therefore have limited value in the community.

Important differences also occur in the outcomes of similar interventions in different healthcare settings. For example, most patients seen in primary care have earlier or milder disease than those referred to hospital. Therefore, the positive predictive value of diagnostic tests in primary care is lower than in secondary care, and invasive investigations may be less justified and less acceptable to patients. Management decisions taken by primary and secondary care doctors may also differ systematically, reflecting different experience and priorities.