Guilt by association

Morris and coworkers in the Thalassemia Clinical Research Network report in this issue of Blood on the suspected association of high tricuspid regurgitant jet velocity (TRV) with mortality in > 300 patients with thalassemia, three-quarters of whom are transfused, and find no relationship.¹ 

Recently, some hematologists (including Morris et al) have been preoccupied by the proposition advanced by Gladwin and colleagues that a cardiac sonar imaging of TRV greater than 2 standard deviations above normal (equal to > 2.5m/s) is associated with hemolysis, anemia, and a poor prognosis in sickle cell disease (SCD).²  The poor prognosis is ascribed to the development of pulmonary hypertension (PH). Given that cardiomegaly and hyperdynamic cardiac contractions are standard in SCD and other chronic anemias including thalassemia (transfused thalassemics are somewhat anemic much of the time between transfusions), it seems likely that “normal” values for TRV should be adjusted upwards in those conditions. Therefore, it seems particularly unwise to rely on TRV to diagnose PH. Parent and colleagues in a well-done study have recently shown by cardiac catheterization that the relationship between the two is at best vestigial at least in SCD, the disease in which the TRV frenzy began.³ 

Hence, it is not at all surprising that Morris et al find no relationship between TRV and mortality in patients with thalassemia.¹  This is not to deny that PH occurs in transfused thalassemics and particularly in untransfused splenectomized patients with thalassemia intermedia and in some other anemias characterized by rapid red cell membrane breakdown and high platelet counts. This has been known for decades. The cause is uncertain but procoagulant “blood dust” is likely to play an important role.

Guilt by association is forbidden in the law, but medicine is an uncertain and often frustrating science. No matter how sophisticated our technology, we physicians often grapple for facts that are beyond our reach. To improve our knowledge and to generate potentially useful hypotheses we may use associations, though the latter may be weak and often unreliable approaches to fact gathering. Physicians are perhaps more comfortable with associations than they should be because our entire approach to history taking and physical examinations actually depends on them. But associations can be very misleading. When we use them in clinical research to define a genetic basis of a complex disease or establish the significance of a laboratory test, we may hoist ourselves on a petard of coincidence. A high TRV and PH may coincide in SCD and thalassemia but TRV is a very poor predictor of PH in those disorders. It is an unreliable screening test of minimal value to the hematologist. Its use should be restricted in chronic anemia to patients actually suspected of having PH on other grounds. Furthermore, the entire construct of clinical associations (hemolysis, anemia, and TRV) in SCD has been seriously questioned by Bunn et al⁴  and by Hebbel.⁵ 

The use of SNP arrays in genome-wide association (GWA) studies in complex multigenic diseases is also highly controversial. Many (including this commentator) hold that most of the results, although statistically significant, are biologically trivial and a waste of effort. But there are clear-cut exceptions. For example, the critical role of BCL11A, a profoundly important regulator of fetal hemoglobin expression, was initially identified in a GWA study conducted by Menzel and colleagues⁶  and recent studies reported on by Pennisi about the role of apparently trivial SNPs in transcription factor binding⁷  might modify the negative views of doubters like me. So as in all things, it is best to keep an open mind, but one must remain wary of association studies to derive principles of pathophysiology and the screening tests that may emerge from them. As is the case with respect to TRV, they are apt to lead one badly astray and to waste valuable research time and effort. Guilt by association is as dangerous in medicine as it is in the law.