Divergence from Hardy Weinberg Equilibrium in Newborn Screening Cohorts for Sickle Hemoglobin
Bibliographic record
Abstract
Abstract Newborn screening (NBS) for hemoglobinopathies was first introduced in the 1970's to prevent infectious complications of homozygous sickle cell disease (hemoglobin [Hb] SS). The frequency of HbSS in newborns can be estimated using carrier rates (heterogygotes), assuming Hardy Weinberg Equilibrium (HWE). The current study examined whether NBS cohorts matched expected HWE distribution, and possible reasons for divergence. For the purpose of this study, all variants other than HbS were considered to be HbA. A total of 82 studies (1956 to 2013) were retrieved, of which 7 were excluded (carrier parents selected or screening sickle test used). Distribution of Hb SS, AS and AA was examined in 75 studies, from the following regions: Sub Saharan Africa n=26, Brazil n=12, USA n=12, EU n=10; Middle East/North Africa n=7, Caribbean n=6, India n=1, Canada n=1. The following screening laboratory methods were used: cellulose acetate electrophoresis (n=22), isoelectric focusing (n=21), high performance liquid chromatography (n=16), filter paper or micro column (n=7), other (n=9). A total of16,377,450 newborns or infants were included. In mixed random models, relative risk (RR) of detecting HbSS compared to expected HWE distribution was 2.06 (95% confidence interval [CI] 1.86, 3.66), p<0.001. In cohorts where HbAS carrier rates was >= 15%, RR was 1.44 (95% CI 1.23, 1.70), p=0.005; if carrier rates were between >=5% and <15%, RR was 1.62 (95% CI 1.20, 2.19), p=0.004; if carrier rates were <5%, RR was 5.74 (95% CI 3.4, 9.78), p<0.001. Thirteen studies provided data by subgroup: place of origin, ethnicity or race. Affected individuals were more likely to cluster in studies with lower HbS gene frequency (figure 1). Conversely, HbSS RR observed compared to expected HWE distribution was highest in populations with lowest overall gene frequency (figure 2). Overall RR for detecting HbAS compared to expected was 0.96 (95% CI 95, 97) p<0.001. Controlling for gene frequency, the Caribbean region was least likely to deviate from the expected HWE distribution, compared to other regions (RR 1.05, 95% CI 1.01, 1.05, P=0.007); cellulose acetate electrophoresis based methods were most likely to deviate from expected HWE distribution, compared to other methods (RR 0.97, 95%CI 0.95, 0.100, p=0.038). Deviation from HWE is commonly observed in NBS cohorts. It is an expected finding when smaller populations (e.g.migration) carrying a gene, exist within a larger population less affected with the same gene. However, even when controlling for gene frequency, regional variations were noted. Reasons may include further variations in population homogeneity, non-random mating within smaller groups (consanguinity), variations in hemoglobin variant distribution (alpha, beta thalassemia, fetal hemoglobin expression). Lab methods may also affect agreement with HWE distribution, as correct classification of non-affected individuals may vary between methods (normal homozygotes, variants and carriers). Divergence from HWE, especially when observed HbSS occurrence is less than expected, or when population Hb S gene distribution is known, may serve as a rapid and inexpensive quality control measure. Further examination of possible reasons for HWE deviation and caution when estimating burden of disease using carrier rates derived from NBS cohorts appear warranted. Figure 1: Distribution of the hemoglobin (Hb) S gene within a population in studies that provided data on subgroups, depending on Hb S gene frequency. Figure 1:. Distribution of the hemoglobin (Hb) S gene within a population in studies that provided data on subgroups, depending on Hb S gene frequency. Figure 2: Relative Risk (RR) of observing Hb SS compared to expected HWE. Diagonal line on left indicate a hypothetical population with a Hb AS carrier rate of 5% that is gradually diluted into a homozygote Hb AA population; diagonal line of right represents a similar hypothetical population with a Hb AS carrier rate of 30%. Figure 2:. Relative Risk (RR) of observing Hb SS compared to expected HWE. Diagonal line on left indicate a hypothetical population with a Hb AS carrier rate of 5% that is gradually diluted into a homozygote Hb AA population; diagonal line of right represents a similar hypothetical population with a Hb AS carrier rate of 30%. Disclosures No relevant conflicts of interest to declare.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.046 | 0.096 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".