A newly developed rapid prediction model based on direct measurement of intact global chains might be an alternative to large-scale phenotypic screening and typing of β-globin variants and β-thalassemia, according to recent research (Clin Chem 2022; doi: 10.1093/clinchem/hvac151).

The model uses a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) platform, which is quicker than the usual methods, and both highly accurate and predictive, according to researchers.

They note that 90% of global β-globin disorder patients live in low- and middle-income countries, which are beset by resource limitations.

In response, the researchers constructed a MALDI-TOF-MS-based approach for identifying various β-globin disorders and classifying thalassemia major (TM) and thalassemia intermedia (TI) patients using 901 training samples with known HBB/HBA genotypes. This approach involves a prediction model for identifying different forms of β-globin disorders in a single MALDI-TOF-MS test based on δ- to β-globin, γ- to α-globin, γ- to β-globin ratios, and/or the abnormal globin-chain patterns.

The researchers validated the accuracy of this method for population screening and clinical classification in two separate cohorts, with 16,172 participants and 201 β-thalassemia patients. The researchers used traditional methods as controls and considered genetic tests the gold standard for testing positive specimens.

The validation study yielded results comparable to standard methods. Clinical specificity was 99.89% for MALDI-TOF-MS, versus 99.71% for the traditional methods. Accuracy was 99.78%, versus 99.16% for the traditional methods. MALDI-TOF-MS sensitivity was higher than the new method, 97.52% versus 88.01%.

The new assay identified 22 additional abnormal hemoglobins in 69 individuals, including 9 novel hemoglobins. The new assay also accurately screened for 9 carriers of deletional hereditary persistence of fetal hemoglobin or δβ-thalassemia. TM and TI were well-classified in 178 out of 201 samples from β-thalassemia patients, researchers reported.


Circulating serum genomic cell-free DNA (ccf-gDNA) may be useful for identifying people at increased risk of developing dementia and worsening cognition and frailty, according to a recent study (J Alz Disease 2022; doi: 10.3233/JAD-220301).

Altered cell homeostasis observed in patients with cognitive decline and frailty leads to cell death, and this turnover leads to release of ccf-gDNA. To see whether serum ccf-gDNA is associated with physical and cognitive decline in older adults, the researchers tested serum from 631 community-dwelling individuals with an average age of 79 who were without cognitive impairment at baseline.

Participants received yearly physical and cognitive testing and had blood drawn once a year over 8 years. The researchers quantified serum ccf-gDNA fragments using digital PCR. They also referenced an array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw, with adjustment for age, sex, race, and education.

In a cross-section analysis, the researchers found that higher ccf-gDNA levels were associated with a lower global cognition score and slower gait speed at the evaluation nearest to blood draw.

Higher ccf-gDNA levels were associated with increased odds of incident dementia (OE 1.27, 95% CI, 1.05, 1.54).

A longitudinal analysis revealed that higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty. For every 100 copies/mL increase in ccf-gDNA, there was a steeper decrease in global cognitive score of 0.11 points per year and a steeper increase in frailty z-score per year of 0.13 points per year.

This study is a first step towards characterizing the role of ccf-gDNA as a blood-based biomarker of cognitive decline and progression of frailty and further underscores the importance of inflammation in the geriatric syndromes of dementia and frailty, the researchers said.


Recent research suggests that in the absence of cystatin C testing, estimated glomerular filtration (eGFR) rate inadequately distinguishes broader risks associated with mild chronic kidney disease (CKD) based on serum creatinine level (JAMA Network Open 2022; doi:10.1001/jamanetworkopen.2022.38300). Kidney function is usually estimated from serum creatinine level, whereas an alternative glomerular filtration marker, cystatin C level, is more closely associated with cardiovascular disease (CVD) and mortality risk.

Researchers evaluated whether testing concordance between eGFR rates based on cystatin C (eGFRcys) and creatinine (eGFRcr) levels would improve risk stratification for future outcomes and whether estimations differ by age.

The researchers ran a prospective population-based cohort study with 428,402 participants and median follow-up of 11.5 years. Participants had eGFRcr greater than or equal to 45 mL/min/1.73 m2, albuminuria (defined as albumin levels less than 30 mg/g), and no preexisting CVD or kidney failure.

The researchers categorized CKD by concordance between eGFRcr and eGFRcys across the threshold for CKD diagnosis, defined as 60 mL/min/1.73 m2. They assessed 10-year probabilities of CVD, mortality, and kidney failure according to CKD status. Multivariable-adjusted Cox proportional hazards models tested associations between CVD and mortality. Area under the receiving operating curve tested discrimination of eGFRcr and eGFRcys for CVD and mortality. The Net Reclassification Index assessed the usefulness of eGFRcr and eGFRcys for CVD risk stratification.

Analyses were stratified by older (65–73 years) and younger (under 65) age groups.

Among 428,402 participants, the median age was 57. Among the 76,629 older participants, there were 9,335 deaths and 5,205 CVD events. Among the 351,773 younger participants, there were 14,776 deaths and 9,329 CVD events. The 10-year probability of kidney failure was less than 0.1%. Regardless of the eGFRcr, the 10-year probabilities of CVD and mortality were low when eGFRcys was more than or equal to 60/mL/min/1.73 m2. With eGFRcys less than 60/mL/min/1.73 m2, 10-year risks were nearly doubled in older adults and more than doubled in younger adults. Use of eGFRcys better discriminated CVD and mortality risk than eGFRcr. Across a 7.5%, 10-year risk threshold for CVD, eGFRcys improved case Net Reclassification Index by 0.7% (95% CI, 0.6%–0.8%) in older people and 0.7% (95% CI, 0.7%–0.8%) in younger people. eGFRcr did not add to CVD risk estimation.

These findings suggest that eGFRcr of 45–59 mL/min/1.73 m2 includes a proportion of individuals at low risk and fails to capture a substantial proportion of those at high risk for CVD and mortality.

The eGFRcys appears to be more sensitive and specific for CVD and mortality risks in mild CKD.