Therneau, Terry M.

Background and aims: The American Gastroenterological Association (AGA) recently launched the Clinical Care Pathway for the Risk Stratification and Management of Patients with NAFLD to identify adults with significant fibrosis. We aimed to examine this pathway’s performance in the US population. Approach and Results: Using the 2017–2018 National Health and Nutrition Examination Survey data, we identified participants aged ≥18 with available Fibrosis‐4 (FIB‐4) score and liver stiffness measurement (LSM) in the absence of other liver diseases. Based on the AGA clinical pathway, FIB‐4 < 1.3 and LSM < 8 kilopascals (kPa) by vibration‐controlled transient elastography (VCTE) are associated with low risk of significant fibrosis. Using these cutoffs, we examined the pathway performance using negative predictive value (NPV) and positive predictive value (PPV) and explored alternative risk‐stratification strategies. There were 2322 participants with available data (projected to 94.2 million US adults). The NPV of LSM ≥ 8 kPa among those with FIB‐4 < 1.3 was 90%, whereas the PPV among those with FIB‐4 1.3–2.67 was 13%. As diabetes was a strong predictor of fibrosis, we propose a simple, alternative strategy to eliminate the indeterminate FIB‐4 range and perform VCTE in those with FIB‐4 ≥ 1.3 and diabetes. This strategy would decrease the number of VCTEs from 14.5 to 4.9 million and increase PPV from 13% to 33% without compromising the NPV among those who did not undergo VCTE. Conclusion: The implementation of the current AGA clinical pathway would lead to overutilization of VCTE. An alternative strategy using FIB‐4 ≥ 1.3 and diabetes to select adults undergoing second‐line testing will improve this pathway’s performance and minimize unnecessary VCTEs.

Background and Aims: The impact of disease progression in NAFLD on liver outcomes remains poorly understood. We aimed to investigate NAFLD progression using longitudinal liver stiffness measurements (LSM) by serial magnetic resonance elastography (MRE) and the association with liver outcomes. Approach and Results: All adult patients with NAFLD who underwent at least two serial MREs for clinical evaluation at Mayo Clinic, Rochester, between 2007 and 2019 were identified from the institutional database. Progression and regression were defined based on LSM change of 19% above or below 19% of initial LSM, respectively, based on Quantitative Imaging Biomarker Alliance consensus. The association between change in LSM and liver‐related outcomes occurring after the last MRE was examined using time‐to‐event analysis. A total of 128 participants underwent serial MREs (53% female, median age 59 years). The median time between paired MREs was 3.4 (range 1–10.7) years. NAFLD progression (LSM = +0.61 kPa/year) was identified in 17 patients (13.3%). NAFLD regression (−0.40 kPa/year) occurred in 35 patients (27.3%). Stable LSM was noted in 76 participants (59.4%). In NAFLD without cirrhosis at baseline ( n = 75), cirrhosis development occurred in 14% of LSM progressors and 2.9% of non‐progressors ( p = 0.059) over a median 2.7 years of follow‐up from the last MRE. Among those with compensated cirrhosis at baseline MRE ( n = 29), decompensation or death occurred in 100% of LSM progressors and 19% of non‐progressors ( p < 0.001) over a median 2.5 years of follow‐up after the last MRE. Conclusions: Noninvasive monitoring of LSM by conventional MRE is a promising method of longitudinal NAFLD monitoring and risk estimation of liver‐related outcomes in NAFLD.

AbstractBackgroundAlzheimer’s disease biomarkers of tau pathology may be assessed by both CSF and PET. Cross‐sectional associations between CSF phosphorylated tau (p‐tau) and tau PET have been studied and regional tau PET SUVR has been shown to have similar diagnostic performance as CSF p‐tau. The association between CSF p‐tau and longitudinal tau PET has not been studied. CSF measures may be thought of as a result of the imbalance of influx vs efflux of soluble tau, whereas, tau PET reflects total tau accumulation into insoluble aggregates to date. We therefore hypothesize that baseline CSF p‐tau may be a leading indicator of future tau PET accumulation.MethodWe identified Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with diagnoses of cognitively unimpaired, mild cognitive impairment, and amnestic dementia who had CSF p‐tau (Elecsys p‐tau [181P]) and subsequent serial tau PET (flortaucipir) exams. The first tau PET scan was within 3 years of the CSF p‐tau collection. A longitudinal pipeline with two‐compartment partial volume correction was used to measure change in tau PET in a temporal‐lobe meta‐ROI (amygdala, fusiform, middle/inferior temporal, entorhinal, and parahippocampal regions) with a composite reference region (eroded supratentorial white matter, pons, and whole cerebellum). Spearman correlation was used to assess the association between CSF p‐tau and annual percent change in tau PET. A linear mixed effects model was fit to assess the association adjusting for age and sex.ResultThe study included 143 participants (76% cognitively unimpaired) (). CSF p‐tau was significantly associated with annual percent change in tau PET overall (Spearman R=0.19, p=0.023) () and after adjusting for age and sex (p<0.001) (). There was nonlinearity in the CSF p‐tau effect, with higher values (>20 pg/mL) having a greater association with annual change in tau PET than lower values.ConclusionIn a group of cognitively unimpaired and impaired participants, CSF p‐tau predicted subsequent tau PET accumulation rate. A threshold effect is suggested with subsequent tau PET accumulation primarily in participants with elevated CSF p‐tau levels near the Mayo threshold of 22 pg/mL.

Abstract Dementia and mortality rates rise inexorably with age and consequently interact. However, because of the major logistical difficulties in accounting for both outcomes in a defined population, very little work has examined how risk factors and biomarkers for incident dementia are influenced by competing mortality. The objective of this study was to examine long-term associations between amyloid PET, APOE ɛ4, sex, education and cardiovascular/metabolic conditions, and hazard and absolute risk of dementia and mortality in individuals without dementia at enrolment. Participants were enrolled in the Mayo Clinic Study of Aging, a population-based study of cognitive ageing in Olmsted County, MN, USA. All were without dementia and were age 55–92 years at enrolment and were followed longitudinally. Predictor variables were amyloid PET, APOE ɛ4 status, sex, education, cardiovascular/metabolic conditions and age. The main outcomes were incident dementia and mortality. Multivariable, multi-state models were used to estimate mortality and incident dementia rates and absolute risk of dementia and mortality by predictor variable group. Of the 4984 participants in the study, 4336 (87%) were cognitively unimpaired and 648 (13%) had mild cognitive impairment at enrolment. The median age at enrolment was 75 years; 2463 (49%) were women. The median follow-up time was 9.4 years (7.5 years after PET). High versus normal amyloid (hazard ratio 2.11, 95% confidence interval 1.43–2.79), APOE ɛ4 (women: hazard ratio 2.24, 95% confidence interval 1.80–2.77; men: hazard ratio 1.37, 95% confidence interval 1.09–1.71), older age and two additional cardiovascular/metabolic conditions (hazard ratio 1.37, 95% confidence interval 1.22–1.53) were associated with the increased hazard of dementia (all P &lt; 0.001). Among APOE ɛ4 carriers with elevated amyloid, remaining lifetime risk of dementia at age 65 years was greater in women [74% (95% confidence interval 65–84%) high and 58% (95% confidence interval 52–65%) moderate amyloid], than men [62% (95% confidence interval 52–73%) high and 44% (95% confidence interval 35–53%) moderate amyloid]. Overall, the hazard and absolute risk of dementia varied considerably by predictor group. The absolute risk of dementia associated with predictors characteristic of Alzheimer’s disease was greater in women than men while at the same time the combination of APOE ɛ4 non-carrier with normal amyloid was more protective in women than men. This set of findings may be attributed in part to different biological effects and in part to lower mortality rates in women.

AbstractBackgroundOptimizing software to measure Flortaucipir (AV‐1451) tau PET SUVR change‐over‐time is crucial for longitudinal observational studies and potential trials of anti‐tau agents. Ideal measurements should have good repeatability (low noise), and should clearly separate clinical cognitive groups.MethodWe compared 456 software methods varying in their use of: two major packages, each with cross‐sectional and longitudinal variants (FreeSurfer and an in‐house pipeline using SPM12, MCALT, and ANTs); three temporal‐lobe target regions (each with/without adjacent WM); seven reference regions; five PVC methods; and two statistics (mean vs. median). We used linear mixed‐effects models to compare methods using scans from 88 Mayo Clinic participants (46 cognitively impaired, 42 impaired, excluding those with symptoms inconsistent with the AD pathology imaged by Flortaucipir), each with three visits with PET and MRI. From these models, we calculated two criteria for each pipeline: relative measurement error (residual from the linear mixed model), and the t‐statistic for testing differences in group‐wise rates of change (which has a Cohen’s d interpretation of effect size for longitudinal data). We plotted both criteria orthogonally, then ranked methods overall according to the average of their ranks on both individual criteria.ResultMethods using the entorhinal cortex target region performed poorly in both criteria (Figure 1). The top 10 methods by the combined criteria (top‐left in Figure 2) all used the Mayo SPM12‐based pipeline with an eroded supratentorial WM (eSWM) or composite (eSWM + pons + cerebellum) reference region. Among them, 9/10 used the longitudinal variant, 8/10 used 2‐compartment PVC, and 7/10 used median. Altogether, our results favored SUVR methods with a longitudinal design (simultaneously calculating all time‐points), a temporal‐lobe meta‐ROI including adjacent WM, a composite reference region, 2‐class voxel‐based (Meltzer) PVC, and median statistics. Methods using GTM‐Tau PVC (Baker et al., Data in Brief, 2017) had the highest group separation but relatively large measurement error, giving them ranks 197 and 199 out of 456 with the joint (average rank) criteria.ConclusionCompared with popular FreeSurfer‐based methods (ranks 176, 258; Figure 2), our top‐ranked approaches approximately halved error in SUVR measurements while maintaining or improving group separation.

BackgroundTo operationalize the National Institute on Aging – Alzheimer's Association (NIA‐AA) Research Framework for Alzheimer's Disease 6‐stage continuum of clinical progression for persons with abnormal amyloid.MethodsThe Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We evaluated persons without dementia having 3 consecutive clinical visits. Measures for cross‐sectional categories included objective cognitive impairment (OBJ) and function (FXN). Measures for change included subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (ΔNBS). We calculated frequencies of the stages using different cutoff points and assessed stability of the stages over 15 months.ResultsAmong 243 abnormal amyloid participants, the frequencies of the stages varied with age: 66 to 90% were classified as stage 1 at age 50 but at age 80, 24 to 36% were stage 1, 32 to 47% were stage 2, 18 to 27% were stage 3, 1 to 3% were stage 4 to 6, and 3 to 9% were indeterminate. Most stage 2 participants were classified as stage 2 because of abnormal ΔOBJ only (44–59%), whereas 11 to 21% had SCD only, and 9 to 13% had ΔNBS only. Short‐term stability varied by stage and OBJ cutoff points but the most notable changes were seen in stage 2 with 38 to 63% remaining stable, 4 to 13% worsening, and 24 to 41% improving (moving to stage 1).InterpretationThe frequency of the stages varied by age and the precise membership fluctuated by the parameters used to define the stages. The staging framework may require revisions before it can be adopted for clinical trials. ANN NEUROL 2021;89:1145–1156

ABSTRACTThere is a high prevalence of blood-borne infections in West Africa. This study sought to determine the seroprevalence of blood-borne infections, including hepatitis B virus (HBV), hepatitis C virus (HCV), HIV, and syphilis, in blood donors in Burkina Faso. Blood donors were recruited from 2009 to 2013 in four major cities in Burkina Faso of urban area (Ouagadougou) and rural area (Bobo Dioulasso, Fada N’Gourma, and Ouahigouya). Serology tests including hepatitis B surface antigen, anti-HCV, anti-HIV, and rapid plasma reagin test were used for screening and were confirmed with ELISA. Disease prevalence was calculated among first-time donors. Incidence and residual risk were calculated from repeat donors. There were 166,681 donors; 43,084 had ≥ 2 donations. The overall seroprevalence of HBV, HCV, HIV, and syphilis were 13.4%, 6.9%, 2.1%, and 2.4%, respectively. The incidence rates (IRs) of HBV, HCV, HIV, and syphilis infection were 2,433, 3,056, 1,121, and 1,287 per 100,000 person-years. There was lower seroprevalence of HBV and HCV in urban area than in rural area (12.9% versus 14.0%, P < 0.001; and 5.9% versus 8.0%, P < 0.001), and no difference in HIV (2.1% versus 2.1%, P = 0.25). The IRs of new HBV, HCV, HIV, and syphilis were 2.43, 3.06, 1.12, and 1.29 per 100,000 person-years, respectively. The residual risk was one per 268 donations for HBV, one per 181 donations for HCV, and one per 1,480 donations for HIV, respectively. In conclusion, this comprehensive study from four blood donation sites in Burkina Faso showed high HBV and HCV seroprevalence and incidence with high residual risk from blood donation.

BackgroundNonalcoholic fatty liver disease (NAFLD) affects 25% of the global population. The standard of diagnosis, biopsy, is invasive and affected by sampling error and inter‐reader variability. We hypothesized that widely available rapid MRI techniques could be used to predict nonalcoholic steatohepatitis (NASH) noninvasively by measuring liver stiffness, with magnetic resonance elastography (MRE), and liver fat, with chemical shift‐encoded (CSE) MRI. Besides, we validate an automated image analysis technique to maximize the utility of these methods.PurposeTo implement and test an automated system for analyzing CSE‐MRI and MRE data coupled with model‐based prediction of NASH.Study TypeProspective.SubjectsEighty‐three patients with suspected NAFLD.Field Strength/SequenceA 1.5 T using a flow‐compensated motion‐encoded gradient echo MRE sequence and a multiecho CSE‐MRI sequence.AssessmentsThe MRE and CSE‐MRI data were analyzed by two readers (5+ and 1 years of experience) and an automated algorithm. A logistic regression model to predict pathology‐diagnosed NASH was trained based on stiffness and proton density fat fraction, and the area under the receiver operating characteristic curve (AUROC) was calculated using 10‐fold cross validation for models based on both automated and manual measurements. A separate model was trained to predict the NASH severity score (NAS).Statistical TestsPearson's correlation, Bland–Altman, AUROC, C‐statistic.ResultsThe agreement between automated measurements and the more experienced reader (R2 = 0.87 for stiffness and R2 = 0.99 for proton density fat fraction [PDFF]) was slightly better than the agreement between readers (R2 = 0.85 and 0.98). The model for predicting biopsy‐diagnosed NASH had an AUROC of 0.87. The NAS‐prediction model had a C‐statistic of 0.85.Data ConclusionWe demonstrated a workflow that used a limited MRI acquisition protocol and fully automated analysis to predict NASH with high accuracy. These methods show promise to provide a reliable noninvasive alternative to biopsy for NASH‐screening in populations with NAFLD.Level of Evidence2Technical Efficacy Stage2

Abstract Objective We aimed to develop a model for accurate prediction of general care inpatient deterioration. Materials and Methods Training and internal validation datasets were built using 2-year data from a quaternary hospital in the Midwest. Model training used gradient boosting and feature engineering (clinically relevant interactions, time-series information) to predict general care inpatient deterioration (resuscitation call, intensive care unit transfer, or rapid response team call) in 24 hours. Data from a tertiary care hospital in the Southwest were used for external validation. C-statistic, sensitivity, positive predictive value, and alert rate were calculated for different cutoffs and compared with the National Early Warning Score. Sensitivity analysis evaluated prediction of intensive care unit transfer or resuscitation call. Results Training, internal validation, and external validation datasets included 24 500, 25 784 and 53 956 hospitalizations, respectively. The Mayo Clinic Early Warning Score (MC-EWS) demonstrated excellent discrimination in both the internal and external validation datasets (C-statistic = 0.913, 0.937, respectively), and results were consistent in the sensitivity analysis (C-statistic = 0.932 in external validation). At a sensitivity of 73%, MC-EWS would generate 0.7 alerts per day per 10 patients, 45% less than the National Early Warning Score. Discussion Low alert rates are important for implementation of an alert system. Other early warning scores developed for the general care ward have achieved lower discrimination overall compared with MC-EWS, likely because MC-EWS includes both nursing assessments and extensive feature engineering. Conclusions MC-EWS achieved superior prediction of general care inpatient deterioration using sophisticated feature engineering and a machine learning approach, reducing alert rate.