Kristin Wuichet

The US Food and Drug Administration recently approved sickle cell disease (SCD) gene therapies that require a contemporaneous cohort to compare their outcomes with those of individuals who did not receive gene therapy. Previously, we developed an automated algorithm to create a contemporaneous cohort of children and adults with SCD using electronic health record data. We tested the hypothesis that the updated Vanderbilt University Medical Center (VUMC) algorithm can identify individuals with SCD with sensitivity and specificity of >95%. In the VUMC health care system, we identified a cohort of 33 141 adults and children of primarily African ancestry who underwent β-globin gene sequencing, with a 1.4% prevalence of SCD (473/33 141). For SCD, the performance of the VUMC algorithm using International Classification of Diseases (ICD) and laboratory data showed a sensitivity of 97.6% (462/473), specificity of 99.9% (32 663/32 668), positive predictive value of 98.9% (462/467), and negative predictive value of 99.9% (32 663/32 674). Three SCD phenotypes account for 98.5% of the individuals in the cohort. The cohort had sensitivities of 96.8% (272/281), 93.7% (136/145), and 85% (34/40) for hemoglobin SS (HbSS)/Hb Sβ0-thalassemia (HbSβ0), HbSC, and HbSβ+, respectively. The cohort had a specificity of 99.9% across all 3 phenotypes: HbSS/HbSβ0, HbSC, and HbSβ+, respectively. We have developed an updated algorithm using ICD and laboratory data that accurately identifies individuals with SCD within a large health care system, and distinguishes HbSS/HbSβ0, HbSC, and HbSβ+.

Recent studies have reached opposing conclusions about whether clonal hematopoiesis (CH) is increased or decreased in patients with sickle cell disease (SCD). Given that CH is typically age-related, its presence in children with SCD could offer unique insights into early-life mutagenesis and disease-related stressors. We tested the primary and secondary hypotheses that children with SCD would have a higher prevalence of CH than age-, sex-, and race-matched children without SCD and that children with hydroxyurea would have a higher CH prevalence than children not treated with hydroxyurea. To address this, we conducted a cross-sectional study in 2 independent cohorts of children aged 0 to 18 years with SCD (N = 1025 and N = 1293, respectively) and a 2957-person matched comparison group. Using a highly sensitive, error-corrected sequencing assay capable of detecting CH at a variant allele frequency of ≥0.5%, we found that children with SCD have a significantly higher prevalence of CH than the comparison group (odds ratio [OR], 4.2; P = 7.4 × 10−13). In addition, CH was not associated with exposure to hydroxyurea therapy (OR, 0.76; P = .44).

The Food and Drug Administration requires contemporaneous controls to compare clinical outcomes for participants receiving experimental gene therapy or gene editing clinical trials. However, developing a contemporaneous cohort of rare diseases requires multiple person-hours. In a single referral center for sickle cell disease, we tested the hypothesis that we could create an automated contemporaneous cohort of children and adults with sickle cell anemia (SCA) to predict mortality. Data were obtained between 1 January 2004 and 30 April 2021. We identified 419 individuals with SCA with consistent medical care defined as followed continuously for >0.5 years with no visit gaps >3.0 years. The median age was 10.2 years (IQR, 1-24 years), with a median follow-up of 7.4 years (IQR, 3.6-13.5 years) and 47 deaths. A total of 98% (274 of 277) of the children remained alive at 18 years of age, and 34.3% (94 of 274) of those children were followed into adulthood. For adults, the median age of survival was 49.3 years. Treatment groups were mutually exclusive and in a hierarchical order: hematopoietic stem cell transplant (n = 22)>regular blood transfusion for at least 2 years (n = 56)>hydroxyurea for at least 1 year (n = 243)>no disease-modifying therapy (n = 98). Compared to those receiving no disease-modifying treatment, those treated with hydroxyurea therapy had a significantly lower hazard of mortality (hazard ratio = 0.38; P = 0.016), but no statistical difference for those receiving regular blood transfusions compared to no disease-modifying therapy (hazard ratio = 0.71; P = 0.440). An automated contemporaneous SCA cohort can be generated to estimate mortality in children and adults with SCA.

Background: The currently known protein sequence space consists of millions of sequences in public databases and is rapidly expanding. Assigning sequences to families leads to a better understanding of protein function and the nature of the protein universe. However, a large portion of the current protein space remains unassigned and is referred to as its “dark matter”. Results: Here we suggest that true size of “dark matter” is much larger than stated by current definitions. We propose an approach to reducing the size of “dark matter” by identifying and subtracting regions in protein sequences that are not likely to contain any domain. Conclusions: Recent improvements in computational domain modeling result in a decrease, albeit slowly, in the relative size of “dark matter”; however, its absolute size increases substantially with the growth of sequence data.