CLN - The Sample
A recent study proves the feasibility of high-throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) applications in a large clinical trial on cardiac risk called ODYSSEY OUTCOMES (J Appl Lab Med 2024; doi: 10.1093/jalm/jfae092).
The current lipid panel — including low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides — lacks the molecular definition to address the residual risk of major adverse cardiovascular events. Apolipoproteins, the functional proteins of lipid metabolism, are potential candidates to fulfill this unmet clinical need. They are molecularly defined and can be measured directly with LC-MS/MS.
To evaluate the clinical performance and effectiveness of a multiplex apolipoprotein (Apo) panel in the context of precision diagnostics, researchers used quantitative clinical chemistry proteomics (qCCP) to measure ODYSSEY OUTCOMES trial patients who had recent acute coronary syndrome. This study is the first qCCP trial at this scale performed in a diagnostic clinical chemistry laboratory to meet test process requirements and predefined analytical performance criteria for clinical medical tests.
The researchers measured serum apolipoproteins from 23,376 samples with a laboratory-developed multiplex apolipoprotein A (Apo A) test on four Agilent LC-MS/MS systems. They designed a fit-for-purpose process with tailored additions that enhanced the accredited laboratory infrastructure and the total testing process. Quality assurance was organized in three steps: system suitability testing, internal quality control evaluation with adjusted Westgard rules to fit a multiplex test, and interpeptide agreement analysis. Data were semiautomatically evaluated with a custom R script.
The researchers performed LC-MS/MS analyses with the following between-run coefficients of variation: for Apo-A, 6.2%; Apo A-I, 2.3%; Apo A-II, 2.1%; Apo A-IV, 2.9%; Apo B, 1.9%; Apo C-I, 3.3%; Apo C-II, 3.3%; Apo C-III, 2.7%; and Apo E, 3.3%. The average interpeptide agreement Pearson r was 0.981.
These results bring the field a step closer to cardiovascular precision diagnostics, according to researchers. They add that having both a routine general clinical chemistry laboratory and research laboratory facilities within the same department was essential for the study’s successful execution.
Study Makes Case for Universal Genetic Testing in New Breast Cancer Patients
Universal genetic testing identifies actionable germline pathogenic breast cancer variants in more than 1 in 5 diagnosed patients, a recent study found (JAMA Open 2024; doi:10.1001/jamanetworkopen.2024.31427).
About 5–10% of breast cancers are associated with an inherited germline pathogenic or likely pathogenic variant (GPV) in a breast cancer susceptibility gene, a situation that could affect therapy recommendations. However, traditional genetic testing criteria miss a meaningful proportion of these cases.
In a cross-sectional study, researchers aimed to evaluate the prevalence and pathological association of GPVs in two groups of breast cancer susceptibility genes (BCSGs) in an ethnically diverse cohort of women with newly diagnosed breast cancer.
The researchers offered genetic counseling to eligible participants with a first diagnosis of invasive breast cancer, including a panel with BRCA1, BRCA2, and PALB2 (B1B2P2), and an optional secondary panel of 14 additional BCSGs. Eligibility criteria included being 18 years of age or older and having a diagnosis of a first primary invasive breast cancer not more than 6 months before the time of referral to the study.
Of 1,017 referred patients, the researchers found 805 eligible patients. Of these, 90.6% consented to testing. Almost two-thirds were of European ancestry. The researchers found 54 GPVs in 53 patients (7.3%), including 39 patients (5.3%) with B1B2P2. They also found 15 patients (2.1%) with six of the 14 secondary panel BCSGs (ATM, BARD1, BRIP1, CHEK2, RAD51D, and STK11). On multivariable analysis, clinical factors independently associated with B1B2P2-positive status were being younger than 40 (odds ratio [OR], 6.83; 95% CI, 2.22–20.90), triple-negative breast cancer (OR, 3.19; 95% CI, 1.20–8.43), high-grade disease (OR, 1.68; 95% CI, 1.05–2.70), and family history of ovarian cancer (OR, 9.75; 95% CI, 2.65–35.85). Of 39 B1B2P2-positive patients, 13 (33.3%) were eligible for poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors.
The researchers wrote that evidence from this and other studies allows them to offer mainstream, oncology-led genetic testing to all new invasive breast cancer patients under age 50, those with TNBC and/or bilateral breast cancer, and those potentially eligible for PARP inhibitors.
Mothers’ HCV Infections Linked to NICU Stay
Maternal hepatitis C virus (HCV) infection is associated with a twofold increase in the odds of neonatal intensive care unit (NICU) admission and a nearly threefold increase in the odds of birth weight below the 5th percentile (Obstet Gynecol 2024; DOI: 10.1097/AOG.0000000000005703).
The researchers evaluated the risk of adverse maternal and neonatal outcomes associated with pregnancies complicated by HCV in a secondary analysis of a multicenter prospective cohort study of HCV infections in pregnancy.
The researchers screened participants for HCV infections with serum antibody tests. At enrollment, they prospectively matched each participant with a positive result with up to two individuals with negative HCV results, by gestational age. Maternal outcomes included gestational diabetes, abruption, preeclampsia or gestational hypertension, cholestasis, and preterm delivery. Neonatal outcomes included jaundice, NICU admission, small-for-gestational-age (SGA) birth weight, and neonatal infection. Infections were either sepsis or pneumonia. The researchers adjusted models for maternal age, body mass index, injection drug use, and maternal comorbidities.
The researchers prospectively matched 249 pregnant women in the case group with 486 individuals in the control group. The groups had significant demographic differences, including race, socioeconomic markers, education, insurance status, and drug and tobacco use, but the frequencies of gestational diabetes, preeclampsia, and abruption in the mother were similar in both groups. Preterm birth was also similar between the two groups.
However, neonates born to case-group mothers were more likely to be admitted to the NICU, with 45.1% of case-group babies going there, compared with 19% in the control group. Case-group babies also were more likely to have SGA birth weights below the 5th percentile, with 6.1% of case-group babies in this category, versus 3.1% in the control group. The researchers saw no increased odds of jaundice or neonatal infection.
Read the full November/December 2024 CLN issue here.