NHLBI: Cooperative Study of Sickle Cell Disease (CSSCD)

Phenotypic heterogeneity is characteristic of sickle cell anemia, a Mendelian disorder caused by homozygosity for the sickle HBB gene (glu6val). Patients have different rates of hemolysis/vasculopathy and viscosity/vasoocclusion-related complications. These complications account for a substantial reduction in life expectancy. In 1994, the median life expectancy for men and women with sickle cell anemia was 42 and 48 years, respectively, and despite many advances in care, the annual mortality still approaches 4%. Fetal hemoglobin (HbF) is one of the most studied markers of severity of sickle cell anemia, and detailed longitudinal measurements were taken on subjects enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD). Cubic root transformation of the median values from follow-up in 848 African American subjects is the phenotype data used in the GWAS of fetal hemoglobin. The analysis was adjusted by sex. Details are in Solovieff et al., Blood 2010 [PMID: 20018918]. To integrate individual disease complications into a comprehensive measure of severity, we developed a model of the associations among clinical and laboratory variables that scored disease severity as the risk of death within 5 years. This network was developed using data obtained from more than 3,400 subjects from the CSSCD, and its accuracy was validated in two unrelated sets of sickle cell patients. Recently, the network was also validated in a small European cohort of patients with sickle cell anemia. We used extreme values of disease severity as cases and control in the GWAS of severity of sickle cell anemia. We conducted the GWAS in 1,265 patients with either "severe" (177) or "mild" disease (1088) based on a network model of disease severity. Details are in Sebastiani et al. Am J Hematol, 2010 [PMID: 20029952].]]>
The analysis describes a genome wide association study of fetal hemoglobin in 846 African Americans with sickle cell anemia from the Cooperative Study of Sickle Cell Disease. Genotype data were generated with the microarray Illumina 610. Median values of repeated measures of fetal hemoglobin were analyzed after a cubic root transformation.Refer to original study Full documentation of the study is available from: https://biolincc.nhlbi.nih.gov/studies/csscd/.]]>
A cooperative group for the study of sickle cell disease was formed in 1977 at the National Institutes of Health (NIH) to organize a multicenter, prospective study of the clinical course of sickle cell disease in patients from the newborn period through adulthood. The primary motivation for the study was the lack of systematically obtained knowledge about this prevalent and costly hereditary disease. Although the molecular and genetic features of sickle cell disease have been known for years and many of its manifestations have been recognized, the clinical course from birth to death is not well understood. This is largely due to the variable degree of severity, the variability of the many manifestations, and the complexity of the interaction of the disease process with other health-related events. Therefore, information obtained was largely anecdotal, retrospective in nature, and lacking statistical validity. There were many unanswered questions about this disease. In 1978, the Division of Blood Diseases and Resources established a multi-institutional study, the Cooperative Study of Sickle Cell Disease, to answer these questions. During the first 10 years of the study (October 1978 through September 1988), 4,085 patients from 23 clinical centers within the United States were enrolled in the study. Patient entry was completed in 1981 for all except patients less than 6 months of age who continued to enter the study through September 1988. Protocol requirements for patients during the original study varied depending on age, phenotype, and time period. In 1989, a 5-year study (Phase 2) to continue follow-up of two patient groups (the infant cohort (patients entered at < 6 months of age in Phase 1) and adults 35 years of age and older) was initiated. During Phase 2, the objectives for the original infant cohort were 1) to identify factors related to overall disease severity, 2) to determine the onset of early organ damage, and 3) to examine risk factors contributing to certain complications and outcomes. The primary areas of interest for this cohort were the brain and lungs. A 5-year follow-up study (Phase 3) was initiated in 1994 to continue collecting these data to allow for longer longitudinal evaluation of factors affecting overall disease severity, brain abnormalities, neurocognitive and psychosocial functioning, and pulmonary dysfunction. Full documentation of the study is available from: https://biolincc.nhlbi.nih.gov/studies/csscd/.]]>

镰状细胞贫血是由镰状HBB基因纯合（谷氨酸6位缬氨酸突变，即glu6val）引发的孟德尔遗传病，其特征为表型异质性。患者的溶血/血管病发生率、血液黏稠度/血管阻塞相关并发症的发病速率存在显著差异，此类并发症可大幅缩短患者的预期寿命。1994年，镰状细胞贫血患者的中位预期寿命男性为42岁，女性为48岁；尽管当前诊疗手段已取得诸多进展，其年死亡率仍接近4%。
胎儿血红蛋白（HbF）是目前研究最为广泛的镰状细胞贫血严重程度标志物之一，镰状细胞病合作研究（Cooperative Study of Sickle Cell Disease, CSSCD）的入组受试者已接受了详细的纵向测量。本研究用于胎儿血红蛋白全基因组关联研究（Genome-Wide Association Study, GWAS）的表型数据，来自848名非裔美国受试者随访数据的中位值经立方根变换后得到，分析过程已按性别进行校正。详细方法参见Solovieff等人发表于《Blood》2010年的研究[PMID: 20018918]。

为将个体疾病并发症整合为综合的严重程度评估指标，我们构建了临床与实验室变量间的关联模型，将疾病严重程度量化为5年内的死亡风险。该网络模型基于CSSCD超过3400名受试者的数据构建，并在两组独立的镰状细胞患者队列中验证了其准确性；近期，该模型还在一个小型欧洲镰状细胞贫血患者队列中得到了验证。我们以疾病严重程度的极端值作为病例组与对照组，开展镰状细胞贫血严重程度的全基因组关联研究。本研究共纳入1265名患者，依据疾病严重程度网络模型分为"重症组"（177人）与"轻症组"（1088人）。详细方法参见Sebastiani等人发表于《American Journal of Hematology》2010年的研究[PMID: 20029952]。

本分析针对来自CSSCD的846名镰状细胞贫血非裔美国受试者的胎儿血红蛋白水平开展全基因组关联研究。基因型数据通过Illumina 610微阵列芯片生成。对重复测量的胎儿血红蛋白中位值经立方根变换后进行分析。具体参见原始研究文献。
本研究完整文档可访问：https://biolincc.nhlbi.nih.gov/studies/csscd/。

1977年，美国国立卫生研究院（NIH）组建了镰状细胞病研究合作组，旨在组织一项多中心前瞻性研究，追踪镰状细胞病患者从新生儿期至成年期的临床病程。本研究的核心动因在于，学界尚缺乏针对这一高发且高花费的遗传性疾病的系统性研究数据。尽管镰状细胞病的分子与遗传学特征已被阐明多年，其诸多临床表现也已得到识别，但从出生到死亡的完整临床病程仍未被充分了解——这在很大程度上源于疾病严重程度的个体差异、多样临床表现的异质性，以及疾病进程与其他健康相关事件间复杂的相互作用。此前相关信息多为零散的个案报道，且以回顾性研究为主，缺乏统计学有效性，该疾病仍存在诸多未解答的问题。

1978年，美国国立卫生研究院血液疾病与资源部启动了多机构研究项目——镰状细胞病合作研究，以解答上述疑问。在研究的前10年（1978年10月至1988年9月），来自美国23个临床中心的4085名患者入组本研究；除6月龄以下的婴儿受试者持续入组至1988年9月外，其余患者的入组工作于1981年完成。原始研究中的方案要求随患者年龄、表型及研究时段有所不同。
1989年，一项为期5年的随访研究（第二阶段）启动，旨在对两组患者队列进行持续追踪：第一阶段入组的婴儿队列，以及35岁及以上的成人队列。第二阶段针对婴儿队列的研究目标包括：1）明确与整体疾病严重程度相关的影响因素；2）确定早期器官损伤的发病时间；3）探究导致特定并发症与不良结局的风险因素。该队列的核心研究领域为大脑与肺部。
1994年，一项为期5年的随访研究（第三阶段）启动，以持续收集上述数据，从而能够对影响整体疾病严重程度、脑部异常、神经认知与社会心理功能以及肺功能异常的相关因素开展更长周期的纵向评估。
本研究完整文档可访问：https://biolincc.nhlbi.nih.gov/studies/csscd/。