Citations

Abstract Background Multianalyte assays with algorithmic analysis (MAAAs), such as the Prostate Health Index (phi), are increasingly utilized for generating disease risk scores. Currently, imprecision and bias in phi are not directly monitored by quality control (QC) assessment of the index but rather by QC assessment of individual components. This may not be adequately controlling for imprecision and bias in the calculated multicomponent phi value itself. Methods Inter- and intra-assay phi precision was compared to precision of the individual component assays. QC measurements from total prostate-specific antigen (PSA), free PSA, and p2PSA were used to calculate a single calculated phi QC metric (PHIc). The frequency of QC failure of PHIc, relative to individual components QC by Westgard rules (13S and 22S), was determined. The effects of varying analyte component assay bias on the resulting PHIc metric were also examined. Results Average measured phi imprecision (6.7% CV) was higher than individual phi analyte component imprecision (3.9–4.5% CV) across 2 Beckman Coulter Unicel DxI 800 instruments. A retrospective examination of PHIc QC over 84 quality control determinations was concurrently carried out for both PHIc and component assay failure patterns, which were dependent on SDs utilized for Westgard evaluation. Finally, reinforcing nonlinear changes in PHIc were observed in select cases of introduced simulated bias of individual component measurements. Conclusions An additional calculated phi QC measure can be introduced to monitor MAAA precision/bias, and in principle calculated index controls may represent a complementary supplemental QC method that could be applied to other MAAA indices.

AbstractINTRODUCTIONUnderstanding the relationship between amyloid beta (Aβ) positron emission tomography (PET) and Aβ cerebrospinal fluid (CSF) biomarkers will define their potential utility in Aβ treatment. Few population‐based or neuropathologic comparisons have been reported.METHODSParticipants 50+ years with Aβ PET and Aβ CSF biomarkers (phosphorylated tau [p‐tau]181/Aβ42, n = 505, and Aβ42/40, n = 54) were included from the Mayo Clinic Study on Aging. From these participants, an autopsy subgroup was identified (n = 47). The relationships of Aβ PET and Aβ CSF biomarkers were assessed cross‐sectionally in all participants and longitudinally in autopsy data.RESULTSCross‐sectionally, more participants were Aβ PET+ versus Aβ CSF− than Aβ PET− versus Aβ CSF+ with an incremental effect when using Aβ PET regions selected for early Aβ deposition. The sensitivity for the first detection of Thal phase ≥ 1 in longitudinal data was higher for Aβ PET (89%) than p‐tau181/Aβ42 (64%).DISCUSSIONAβ PET can detect earlier cortical Aβ deposition than Aβ CSF biomarkers. Aβ PET+ versus Aβ CSF− findings are several‐fold greater using regional Aβ PET analyses and in peri‐threshold‐standardized uptake value ratio participants.Highlights Amyloid beta (Aβ) positron emission tomography (PET) has greater sensitivity for Aβ deposition than Aβ cerebrospinal fluid (CSF) in early Aβ development. A population‐based sample of participants (n = 505) with PET and CSF tests was used. Cortical regions showing early Aβ on Aβ PET were also used in these analyses. Neuropathology was used to validate detection of Aβ by Aβ PET and Aβ CSF biomarkers.

Abstract Background Patients with sporadic or hereditary Medullary Thyroid Carcinoma (MTC) often undergo total thyroidectomy and lymph node dissection, with postoperative surveillance relying on serum calcitonin levels and ultrasound examinations. According to American Thyroid Association (ATA) guidelines, detectable levels of serum calcitonin and Carcinoembryonic Antigen (CEA) post-thyroidectomy suggest potential disease persistence or recurrence, necessitating frequent monitoring for early detection. This study sought to reassess the role of postoperative calcitonin levels in identifying possible tumor recurrence. Methods A retrospective analysis was conducted using Siemens Atellica to test calcitonin levels in 562 samples collected between 09/27/2022 and 08/11/2023, at least 3 months post-total thyroidectomy. Imaging studies performed within 6 months of the calcitonin assessment were also reviewed. Sample pools with calcitonin concentrations near 3.00 and 5.00 pg/mL were utilized to determine the limit of quantification (LoQ). CEA results were included for comparison. Additionally, 16 serum samples were analyzed using the Roche Cobas system at a reference laboratory. Results Precision analysis around 3.00 and 5.00 pg/mL revealed coefficients of variation (CVs) of 16.49% and 8.87%, respectively. Comparison of calcitonin levels between Siemens Atellica and Roche Cobas systems demonstrated consistent levels < 5.00 pg/mL in 15 out of 16 samples, indicating alignment and reliability between the platforms. A calcitonin cutoff of 1.89 pg/mL yielded 43% sensitivity and 67% specificity, while a cutoff of 5.00 pg/mL resulted in 0% sensitivity and 100% specificity. Conclusions Our findings suggest that a 5 pg/mL calcitonin cutoff on the Siemens Atellica platform may be suitable for identifying tumor persistence or recurrence in post-thyroidectomy patients within our institution. However, individual laboratories should establish their LoQ criteria when interpreting calcitonin levels for postoperative monitoring of tumor recurrence.

Abstract There is increasing interest in Alzheimer’s disease related plasma biomarkers due to their accessibility and scalability. We hypothesized that integrating plasma biomarkers with other commonly used and available participant data (MRI, cardiovascular factors, lifestyle, genetics) using machine learning (ML) models can improve individual prediction of cognitive outcomes. Further, our goal was to evaluate the heterogeneity of these predictors across different age strata. This longitudinal study included 1185 participants from the Mayo Clinic Study of Aging who had complete plasma analyte work-up at baseline. We used the Quanterix Simoa immunoassay to measure neurofilament light, Aβ1–42 and Aβ1–40 (used as Aβ42/Aβ40 ratio), glial fibrillary acidic protein, and phosphorylated tau 181 (p-tau181). Participants’ brain health was evaluated through gray and white matter structural MRIs. The study also considered cardiovascular factors (hyperlipidemia, hypertension, stroke, diabetes, chronic kidney disease), lifestyle factors (area deprivation index, body mass index, cognitive and physical activities), and genetic factors (APOE, single nucleotide polymorphisms, and polygenic risk scores). An ML model was developed to predict cognitive outcomes at baseline and decline (slope). Three models were created: a base model with groups of risk factors as predictors, an enhanced model included socio-demographics, and a final enhanced model by incorporating plasma and socio-demographics into the base models. Models were explained for three age strata: younger than 65 years, 65–80 years, and older than 80 years, and further divided based on amyloid positivity status. Regardless of amyloid status the plasma biomarkers showed comparable performance (R² = 0.15) to MRI (R² = 0.18) and cardiovascular measures (R² = 0.10) when predicting cognitive decline. Inclusion of cardiovascular or MRI measures with plasma in the presence of socio-demographic improved cognitive decline prediction (R² = 0.26 and 0.27). For amyloid positive individuals Aβ42/Aβ40, glial fibrillary acidic protein and p-tau181 were the top predictors of cognitive decline while Aβ42/Aβ40 was prominent for amyloid negative participants across all age groups. Socio-demographics explained a large portion of the variance in the amyloid negative individuals while the plasma biomarkers predominantly explained the variance in amyloid positive individuals (21% to 37% from the younger to the older age group). Plasma biomarkers performed similarly to MRI and cardiovascular measures when predicting cognitive outcomes and combining them with either measure resulted in better performance. Top predictors were heterogeneous between cross-sectional and longitudinal cognition models, across age groups, and amyloid status. Multimodal approaches will enhance the usefulness of plasma biomarkers through careful considerations of a study population’s socio-demographics, brain and cardiovascular health.

Abstract INTRODUCTION We aimed to evaluate clinical interpretation cutpoints for two plasma phosphorylated tau (p‐tau)217 assays (ALZpath and Lumipulse) as predictors of amyloid status for implementation in clinical practice. METHODS Clinical performance of plasma p‐tau217 against amyloid positron emission tomography status was evaluated in participants with mild cognitive impairment or mild dementia ( n = 427). RESULTS Using a one‐cutpoint approach (negative/positive), neither assay achieved ≥ 90% in both sensitivity and specificity. A two‐cutpoint approach yielding 92% sensitivity and 96% specificity provided the desired balance of false positives and false negatives, while categorizing 20% and 39% of results as indeterminate for the Lumipulse and ALZpath assays, respectively. DISCUSSION This study provides a systematic framework for selection of assay‐specific cutpoints for clinical use of plasma p‐tau217 for determination of amyloid status. Our findings suggest that a two‐cutpoint approach may have advantages in optimizing diagnostic accuracy while minimizing potential harm from false positive results. Highlights Phosphorylated tau (p‐tau)217 cutpoints for detection of amyloid pathology were established. A two‐cutpoint approach exhibited the best performance for clinical laboratory use. p‐tau217 assays differed in the percentage of results categorized as intermediate.

Abstract Context Tumor-induced osteomalacia (TIO) is a rare condition with evidence mostly derived from case reports and case series. Objective We aimed to describe the clinical characteristics of a large cohort of patients diagnosed with TIO, with a focus on patients with nonlocalizing and malignant TIO. Methods This is a retrospective cohort of patients with TIO in an academic medical center, diagnosed between January 1998 and May 2023. We describe their demographics, biochemistries, tumor features, localization, treatment, and complications. Results Of 68 patients diagnosed with TIO, 49 (72%) were localizing and 5 (7.4%) were malignant. Of 50 patients who attempted localizing procedures, 29 (58%) achieved cure. Twenty (40%) had persistent disease due to the wrong tumor targeted, or refractory or recurrent tumors, despite up to 6 procedural attempts. There was no difference in demographics, phosphorus, or baseline fibroblast growth factor-23 (FGF23) levels between localizing vs nonlocalizing groups, and malignant vs nonmalignant groups. The lower extremity was the commonest site of localization (37%), with 47% in bone and 53% in soft tissue. Sixty percent of malignant cases were located in the trunk. Tumor size correlated with peak FGF23 (R = 0.566, P < .001) but was not associated with malignancy risk (P = .479). A cut-off FGF23 of >20 times upper limit of normal in the presence of normal renal function (P = .025) and recurrence after initial cure (P = .013) were factors significantly associated with malignancy. The nonlocalizing group had lower survival than the localizing group (P = .0097). Conclusion TIO is a condition with significant morbidity. Very high FGF23 levels and disease recurrence are associated with malignant disease. Reasons behind the observation of higher mortality in nonlocalizing TIO should be further explored.