Finally, a consensus statement on sickle cell disease manifestations: a critical step in improving the medical care and research agenda for individuals with sickle cell disease.

The combined effort of the investigators from the Comprehensive Sickle Cell Disease Centers should be applauded for their mission to establish standard definitions of medical complications associated with sickle cell disease. Their accomplishment, published in this issue of American Journal of Hematology, stands as a landmark for both clinical and translational research in sickle cell disease [1]. Far too often, families, healthcare providers, and clinicians are compelled to compare the results from one study to another without knowing whether the primary endpoints are the same. Even worse, the same presentation of a sickle cell complication is often clinician dependent. For example, a child who presents with a new radiodensity on radiograph, fever, and wheezing may be discharged 2 days later with a diagnosis of bronchiolitis by one physician, yet the same presentation may be called acute chest syndrome by another. Patients and their families are only confused when these inconsistencies persist, resulting in miscommunication and distrust. A list of the various definitions of acute chest syndrome used by the six most commonly cited manuscripts is described in Table I. Until the article published by Ballas et al., none of the previous definitions addressed the severity of the episode or whether the pulmonic process was unrelated to sickle cell disease. In addition to improving communication and clinical care for patients, this body of work will facilitate the emerging field of genetics, genomics, and proteomics in sickle cell disease. Trying to perform genotype and phenotype studies without standard definitions of phenotypes has been a challenge, particularly when candidate gene analyses are completed with the almost obligatory requirement of at least one replication cohort to validate findings. Few grants in this field of study provide sufficient funds for both a discovery and replication cohort. Thus, many investigators in this area of research have been met with the challenge of identifying a colleague that will agree to share their data for a confirmatory candidate gene analysis, only later to be disappointed when they discover that their definitions of the phenotypes of interest are not similar enough to combine. Investigators have had similar frustration with the relatively few genomic-wide association studies that have been completed on sickle cell disease. Although, these challenges will still exist for the previously funded studies, the publication by Ballas et al. will provide a valuable starting point for defining the phenotypes of interest for future studies, including clinical trials that concomitantly collect biological samples for genotype–phenotype studies. Identifying a common language for the various manifestations and complications of sickle cell disease should augment the nascent field of health services research in sickle cell disease. All too often, such investigations have been limited to retrospective chart reviews or large data systems. Further, many of the investigators are not hematologists, thus they have relied on the confusing and sometimes conflicting literature defining sickle cell disease phenotypes. A critical next step is the appropriate governance of the International Classification of Disease (ICD) to review specific definitions relating to sickle cell disease and, when appropriate, incorporate these definitions. Subsequently, the major causes of hospitalization for sickle cell disease (pain, acute, and chest syndrome) will have a uniform definition for billing purposes. An important downstream implication of such an activity would be the ease of comparing health outcomes on a regional, national, and even international level based on well-established ICD classifications. Despite the strengths of the seminal effort to standardize definitions of sickle cell disease, there are some deficits. The authors did not provide a description of how the consensus was reached. A common approach for reaching consensus, such as the Delphi method, was not used. Briefly, the Delphi method is a technique that includes a facilitator and a group of experts that circulate a statement or opinion for several iterations until a consensus is reached. Thus, we are unsure of the inherent biases that may have occurred in reaching consensus. Additionally, no systematic approach for identifying the pertinent literature was described; therefore, replication of how they identified the critical references cannot be done. Further, although, hematologists in Comprehensive Sickle Cell Disease Centers are the primary healthcare providers for a large number of patients with sickle cell disease, the majority of patients with sickle cell disease are not cared for by hematologists; thus, inclusion of a diverse body of specialists, generalists, and nurses would have only strengthened the quality and generalizability of the definitions. Perhaps the most notable omission in the consensus statement is the absence of formal involvement from individuals and their families with sickle cell disease. The importance of including individuals with sickle cell disease cannot be overemphasized, as they provide unique insight to the severity, evolution, and resolution of sickle cell disease-related complications. We can only speculate that the inclusion of individuals with sickle cell disease, particularly when defining acute pain episodes may have resulted in a broadening of the definition proposed by Ballas et al. When asked to keep a daily diary, adults with sickle cell disease