The venerable medical tradition of postmortem research would seem to be poised for a quantum leap in this era of molecular science, but old provisos and emergent issues must clearly be taken into account.
On 9 January 2008, Akira Sawa of Johns Hopkins University and Marquis Vawter of the University of California, Irvine, led an SRF online discussion of the fine art of generating and interpreting reliable gene expression data in psychiatric research. We invite you to read their background text below, along with an extensive comment by Vawter on several recent papers, particularly one in the Journal of Neuroscience Methods by Christine Miller and colleagues at Johns Hopkins University and the Stanley Medical Research Institute. We then ask that you share your ideas, warnings, horror stories, and other useful information in the form of a comment.
Background Text By Akira Sawa and Marquis Vawter
The purpose of this forum is to discuss factors that impact gene expression profiles in postmortem human brain in the context of microarray, quantitative PCR, in-situ hybridization, and other expression assessment methods.
The pathophysiology of several psychiatric disorders has been extensively studied using postmortem human brains. Enormous molecular information has been obtained from autopsied brains from schizophrenia patients through microarray and proteomic approaches. However, there are caveats to the use of this tissue as well: schizophrenia appears to be a disorder of neurodevelopmental origin; thus, major pathological events that affect neurodevelopment may be compensated for at later stages, such that they would not be seen or detected in autopsied brains. In addition, mechanisms and processes of brain maturation may be different between patients with schizophrenia and controls. More practically, confounding factors such as medication, smoking, and diet must be considered in studying autopsied brains. Gene expression profiles are affected by RNA quality, fixation, agonal factors, postmortem interval, as well as freeze-thaw effects of autopsied brains.
Thus, we plan to discuss methodological approaches for quality control in postmortem brain gene expression studies, as well as data interpretation, alternative approaches, and subject selection or matching. Our discussion will mainly focus on studies of gene expression profiles, since whole genome studies have been conducted. Similar strategies may also refer to studies targeting protein and peptide profiling.
Some provisional questions for discussion will be
1. What are the reliable parameter(s) for quality control of gene expression profiling with postmortem brains?
2. What are the appropriate strategy(ies) in data analysis and interpretation, considering possible confounding factors?
3. How can we address molecular changes associated with neurodevelopment in the autopsied brains? How can we address the question of possible differences in brain maturation and aging between patients and controls?
4. What types of tissues are to be considered as alternatives to autopsied brains?
5. What types of brain banks or collections are to be developed in the research community?
6. What kinds of data sharing systems are expected to promote research in the field?
Read Mark Vawter's comment on several recent postmortem methods papers.