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In this work, we aimed to establish subgroups of clinical severity in a global cohort of β-thalassemia through unsupervised random forest (RF) clustering. We used a large global dataset of 7910 β-thalassemia patients and evaluated 19 indicators of phenotype severity (IPhS) to determine their contribution and relatedness in grouping β-thalassemia patients into clusters using RF analysis. RF clustering suggested that three clusters with minimal overlapping exist (classification error rate: 4.3%), and six important IPhS were identified: the current age of the patient, the mean serum ferritin level, the age at diagnosis, the age at first transfusion, the age at first iron chelation, and the number of complications. Cluster 3 represented patients with early initiation of transfusion and iron chelation, considerable iron overload, and early mortality from heart failure. Patients in Cluster 2 had lower serum ferritin levels, although they had a higher number of complications manifesting overtime. Patients in Cluster 1 represented a subgroup with delayed or absent transfusion and iron chelation, but with a high morbidity rate. Hepatic disease and cancer were dominant causes of death in patients in Cluster 1 and 2. Our findings established that patients with β-thalassemia can be clustered into three groups based on six parameters of phenotype severity. [ABSTRACT FROM AUTHOR]

Summary: In β‐thalassaemia, the severity of inherited β‐globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long‐term outcomes remain limited. We analysed data from 2109 β‐thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β0/β0, β0/β+, β+/β+, β0/β++, β+/β++, and β++/β++. Patients were followed from birth until death or loss to follow‐up. The median follow‐up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β0 and β+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β0/β0, β0/β+, or β+/β+ had a 2·104‐increased risk of death [95% confidence interval (CI): 1·176–3·763, P = 0·011] and 2·956‐increased odds of multiple morbidity (95% CI: 2·310–3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β‐thalassaemia and suggests inclusion of both β+ and β0 mutations in strata of greatest severity. [ABSTRACT FROM AUTHOR]

Summary: The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion‐dependent thalassaemia (TDT)], Group B [transfused non‐TDT (NTDT)] and Group C (non‐transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left‐ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment. [ABSTRACT FROM AUTHOR]

Introduction: Detection of β-thalassemia trait or carriers (β-TT) depends significantly on an increase in Hemoglobin A2 (HbA2) levels, which is found at low levels (<3%) in normal healthy individuals and elevated levels (≥3.5%) in β-TT individuals. The study was designed to evaluate the reliability of the diagnostic parameter HbA2 in the differentiation of β-TT and non-β-TT in Saudis.Methods: The widely used high performance liquid chromatography (Variant II Bio-Rad) was used to measure HbA2 levels in blood. Sanger sequencing was used to screen the variation in globin genes (HBB, HBD, HBA1, and HBA2). All the study subjects were divided into βTT and non-βTT (wild) categories based on the presence or absence of HBB variations and further sub-divided into false positive, true positive, false negative, and true negative, based on HbA2 values.Results: Out of 288 samples, 96 had HBB gene mutations. Of the 96 β-TT samples, sickle cell trait (SCT) samples (n = 58) were excluded, while the remaining (38 β-TT) were included in the detailed analysis: seven subjects with the HBB mutation had normal HbA2 (<3%), and three were borderline (3.1-3.9%). The remainder (n = 28) had an elevated HbA2 level (>4%). Based on HbA2 analysis alone, both these groups would be incorrectly diagnosed as normal. Similarly, of the 189 non-β-TT samples, 179 had normal HbA2, eight had borderline HbA2, and two had a HbA2 level above 4%. Based on HbA2 analysis alone, borderline and >4% HbA2 individuals, negative for β-TT, can be incorrectly diagnosed as carriers.Conclusion: Given the percentage of samples falling in the HbA2 "borderline" and "normal" categories, it can be concluded that HbA2 has a measure of unreliability in the diagnosis of β-thalassemia carriers. [ABSTRACT FROM AUTHOR]

The regions of Al-Qatif and Al-Ahssa in the Eastern Province of Saudi Arabia are known for their high prevalence of hemoglobinopathies, including β-thalassemia and sickle cell anemia. Previously, the a-gene deletion has been demonstrated as highly prevalent among populations residing in these two regions. The present study was conducted in order to investigate the implications of the a-globin gene deletion on fetal hemoglobin (HbF) and hemoglobin α2 (HbA2) concentrations in patients with transfusion-dependent β-thalassemia. A total of 166 Saudi patients with transfusion-dependent β-thalassemia and 337 healthy Saudi patients were included in the study. The -α3.7, -α4.2, --FIL, --SEA, --MED and --(20.5) gene deletions were identified using multiplex α-globin deletion polymerase chain reaction. The present study revealed that the -α3.7 gene deletion is the most prevalent (43.5%) in the Saudi populations that were analyzed and is characterized by the deletion of 3,804 base pairs. Numerous genotypes, namely -3.7α2/α1α2, -3.7α2/α1α12, -3.7α2/-3.7α2, -3.7α2HphI/α1α2 HphI, -3.7α2/α1 -4.2, -3.7α2/α1 polyA-1α2, -3.7α12/α1α12, -- FIL/-3.7α2 and -3.7α2/-3.7α2 Hb Villiers le Bel were also identified in the investigated population. Furthermore, a gradual increase in the concentration of HbF and HbA2 in patients with β-thalassemia and the number of α-gene deletions was demonstrated; whereas in healthy patients the level of HbA2 was demonstrated to decrease as the number of α-gene deletions increased. Therefore, it can be concluded that the high HbF concentration in the present study is predominantly associated with other mutations associated with β-thalassemia rather than α-globin deletions. Furthermore, the results of the present study also revealed novel α-gene deletion genotypes prevalent in the population studied, namely α1α2/α1α2 HphI, α1α2 HphI/α1α2 HphI, α1α2/α1α² Hb Handsworth, -3.7α2 HphI/α1α² HphI, -3.7α2/-3.7α2 Hb Villiers le Bel and --MED/α1α2 HphI. [ABSTRACT FROM AUTHOR]

Introduction: Elevated HbA2 (hemoglobin A2) level is considered the most reliable hematological parameter for the detection of β-thalassemia carriers. However, some carriers are difficult to recognize because the level of HbA2 is not in the distinctive carrier range, i.e. 4.0-6.0%; instead, some carriers have HbA2 levels between normal and carrier levels, i.e. borderline HbA2 (HbA2 = 3.1-3.9%). Studies have shown that variations in the erythroid Krüppel-like factor (KLF1) gene lead to borderline HbA2 in β-thalassemia carriers from various populations. The incidence of borderline HbA2 in Saudis is high.Material and methods: To confirm the influence of variations in KLF1, HBA1, HBA2 and HBB genes for the reduction of the level of HbA2 in Saudi β-thalassemia carriers, we performed a direct sequence analysis of KLF1, HBA1, HBA2 and HBB genes from 212 healthy Saudis (88 subjects: HbA2 < 3; 72 subjects: HbA2 = 3.1 to 3.9; 52 subjects HbA2 > 4.3).Results: The presence of the borderline HbA2 level is not specific to any type of β-thalassemia variation or β+-thalassemia variations in Saudis. Two exonic (c.304T>C and c.544T>C) and two 3' untranslated region (3'UTR) (c.*296G>A and c.*277C>G) variations have been identified in the KLF1 gene for the first time from an Arab population. None of these four variations in KLF1 genes are significantly associated with the Saudis with borderline HbA2. α Globin genotype, -α23.7/α1α2, is found to be the most frequent (55.55%) among healthy Saudis with borderline HbA2 compared with the other groups (HbA2 < 3 = 20.45%; HbA2 > 4.3 = 13.51%).Conclusions: Further studies are necessary to determine the influence of other factors on the presence of borderline HbA2 in 41.67% of Saudis. [ABSTRACT FROM AUTHOR]