2,4 What is the best strategy to improve phenotype identification? The genetic validity of the current customary criteria for standardized diagnosis has not been demonstrated. We have suggested two complementary strategies for finding genetically valid traits: one involves a description of the affected subjects; and the other involves the identification of vulnerability traits in nonaffected relatives of affected individuals, ie, the Inhibitors,research,lifescience,medical endophenotypic approach. The first strategy utilizes affected individuals and is called the candidate symptom approach. It is analogous

to the candidate gene approach as applied in molecular biology. The candidate symptom approach would identify several stringent clinical characteristics hypothetically associated with a disease genotype and show a pattern of inheritance related Inhibitors,research,lifescience,medical more robustly

to the narrow characteristics than to the diagnosis. Identification of specific subforms of the disorder would lead to identification of homogeneous families, which are more appropriate for linkage studies. The second strategy emphasizes the need to use broader approaches, such as related biochemical, neurophysiological, neuroanatomical, Inhibitors,research,lifescience,medical cognitive, and/or truly neuropsy chological markers, to identify pertinent phenotypes in nonaffected relatives carrying vulnerability genes. These subclinical associated traits, endophenotypes, might be valuable for identifying common alleles with nonspecific and moderate effects on disease risk. Thus, endophenotypes serve to better define the trait or its underlying genetic mechanism.47 To meet criteria for a marker trait, an endophenotype should Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical be measured

in an objective and cost-effective fashion among clinically unaffected relatives of patients, should occur before the onset of illness, should run in families, and should be associated with increased risk of clinical illness. This strategy is recommended for psychiatric disorders in which symptoms occur as the consequence of an interaction between several vulnerability factors, each having good genetic validity but not thorough necessarily disease-specificity. The candidate symptom strategy Target symptoms that Carfilzomib could allow the identification of a homogeneous form of the illness (ie, candidate symptoms) should fulfill the following criteria: they should show good concordance rates among affected monozygotic twins and should be correlated in pairs of affected siblings.48 This strategy has already proven helpful in the identification of subgroups in complex disorders other than psychiatric disorders. For example, subdivision according to age at onset has been particularly efficient in clarifying genetic heterogeneity in dementias of the Alzheimer’s type.