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When sequence detection predates disease, or sequence copy number correlates with severity of disease or pathology, the sequence-disease association is more likely to be a causal relationship. The nature of the microorganism inferred from the available sequence should be consistent with the known biological characteristics of that group of organisms. Tissue-sequence correlates should be sought at the cellular level: efforts should be made to demonstrate specific in situ hybridization of microbial sequence to areas of tissue pathology and to visible microorganisms or to areas where microorganisms are presumed to be located. These sequence-based forms of evidence for microbial causation should be reproducible.
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