Discordant Analysis Research Articles

Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study.

Emerging evidence suggests that remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease (ASCVD). We aimed to estimate RC-related risk beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in patients without known ASCVD. We pooled data from 17 532 ASCVD-free individuals from the Atherosclerosis Risk in Communities study (n = 9748), the Multi-Ethnic Study of Atherosclerosis (n = 3049), and the Coronary Artery Risk Development in Young Adults (n = 4735). RC was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in RC vs. LDL-C discordant/concordant groups using difference in percentile units (>10 units) and clinically relevant LDL-C targets. The mean age of participants was 52.3 ± 17.9 years, 56.7% were women and 34% black. There were 2143 ASCVD events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log RC was associated with higher ASCVD risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.45-1.89]. Moreover, the discordant high RC/low LDL-C group, but not the low RC/high LDL-C group, was associated with increased ASCVD risk compared to the concordant group (HR 1.21, 95% CI 1.08-1.34). Similar results were shown when examining discordance across clinical cutpoints. In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of RC association with ASCVD, surprisingly beyond apoB, and the potential value of targeted RC-lowering in primary prevention need to be further investigated.

A retrospective analysis of discordances between international normalized ratio (INR) self-testing and INR laboratory testing in a pediatric patient population.

The lack of quality control procedures for home point-of-care (POC) international normalized ratio (INR) devices is a concern. Concomitant laboratory and POC INR testing may be proposed to overcome the lack of quality control. However, a difference between the POC INR and the laboratory INR is not necessarily due to failure of the POC device. This study aimed to identify variables associated with a significant deviation between the POC INR and the laboratory INR. Children included in this retrospective cohort study performed at least one concomitant laboratory and POC INRs. Clinical and laboratory variables were assessed for an association with significant deviation within pairs of INR. A significant deviation was noted for 30 (15.3%) of the 196 pairs of INR measurements from 124 children. Relative to patients without deviations, patients with deviations were younger (odds ratio =0.91; P=.020), less experienced in the use of POC INR devices (odds ratio =0.89; P=.098), and more likely to have received an INR result from a laboratory using animal thromboplastin (odds ratio =2.81 vs. 0.37 for laboratories using human thromboplastin; P=.016). In a multivariate analysis, younger age and the laboratory's use of animal thromboplastin were associated with significant deviations. Although most children had coherent pairs of INR values, the occurrence of deviations raises the question of the origin of the thromboplastin used in the laboratory and emphasizes the need to provide specific quality control procedures for POC INR devices.

The role of familial confounding in the associations of physical activity, smoking and alcohol consumption with early exit from the labour market

We investigated the associations between health behaviors and sustainable working life outcomes including all-cause disability pension, disability pensions due to musculoskeletal and mental diagnoses and unemployment. The role of familial factors behind these associations was studied by analysing discordant twin pairs. Our data included Swedish twins born in 1925–1986 (51891 twin individuals). Baseline data based on two independent surveys in 1998–2003 and 2005–2006 for health behaviors were linked to national registers on disability pension and unemployment until 2016. Cox proportional hazards models for hazard ratios (HR) with 95% confidence intervals (CI) were estimated for the whole sample adjusting for covariates. Analyses of health behavior discordant twin pairs (n = 5903 pairs) were conducted using conditional Cox models. In the whole cohort, the combination of healthy behaviors was associated with lower risk for all-cause disability pension, disability pension due to musculoskeletal diagnoses or mental diagnoses, and for unemployment (HRs 0.56–0.86, 95% CIs 0.51–0.92) as did being physically active (HRs 0.69–0.87, 95% CI 0.65–0.92). The discordant pair analyses confirmed the lower risk among those having healthy behaviors (HR 0.70–0.86) or being physically active (HR 0.86–0.87) for all-cause disability pension, disability pension due to musculoskeletal diagnoses, and for unemployment. To conclude, controlling the effects of covariates or familial confounding (i.e. discordant twin pair analyses) shows that being physically active or having several healthy behaviors predict better working life outcomes. This points towards independent association between healthy behavior and longer working life.

18F-FDG PET/CT versus Diagnostic Contrast-Enhanced CT for Follow-Up of Stage IV Melanoma Patients Treated by Immune Checkpoint Inhibitors: Frequency and Management of Discordances over a 3-Year Period in a University Hospital.

Aim: To perform a comprehensive analysis of discordances between contrast-enhanced CT (ceCT) and 18F-FDG PET/CT in the evaluation of the extra-cerebral treatment monitoring in patients with stage IV melanoma. Materials and methods: We conducted a retrospective monocentric observational study over a 3-year period in patients referred for 18F-FDG PET/CT and ceCT in the framework of therapy monitoring of immune checkpoint (ICIs) as of January 2017. Imaging reports were analyzed by two physicians in consensus. The anatomical site responsible for discordances, as well as induced changes in treatment were noted. Results: Eighty patients were included and 195 pairs of scans analyzed. Overall, discordances occurred in 65 cases (33%). Eighty percent of the discordances (52/65) were due to 18F-FDG PET/CT scans upstaging the patient. Amongst these discordances, 17/52 (33%) led to change in patient’s management, the most frequent being radiotherapy of a progressing site. ceCT represented 13/65 (20%) of discordances and induced changes in patients’ management in 2/13 cases (15%). The most frequent anatomical site involved was subcutaneous for 18F-FDG PET/CT findings and lung or liver for ceCT. Conclusions: Treatment monitoring with 18F-FDG PET/CT is more efficient than ceCT and has a greater impact in patient’s management.

Lineage-specific vs. universal: A comparison of the Compositae1061 and Angiosperms353 enrichment panels in the sunflower family.

PremisePhylogenetic studies in the Compositae are challenging due to the sheer size of the family and the challenges they pose for molecular tools, ranging from the genomic impact of polyploid events to their very conserved plastid genomes. The search for better molecular tools for phylogenetic studies led to the development of the family‐specific Compositae1061 probe set, as well as the universal Angiosperms353 probe set designed for all flowering plants. In this study, we evaluate the extent to which data generated using the family‐specific kit and those obtained with the universal kit can be merged for downstream analyses.MethodsWe used comparative methods to verify the presence of shared loci between probe sets. Using two sets of eight samples sequenced with Compositae1061 and Angiosperms353, we ran phylogenetic analyses with and without loci flagged as paralogs, a gene tree discordance analysis, and a complementary phylogenetic analysis mixing samples from both sample sets.ResultsOur results show that the Compositae1061 kit provides an average of 721 loci, with 9–46% of them presenting paralogs, while the Angiosperms353 set yields an average of 287 loci, which are less affected by paralogy. Analyses mixing samples from both sets showed that the presence of 30 shared loci in the probe sets allows the combination of data generated in different ways.DiscussionCombining data generated using different probe sets opens up the possibility of collaborative efforts and shared data within the synantherological community.

Analysis of discordance between HbA1c and FPG criteria for dysglycemia screening in physical examination individuals

The general data, blood routine, liver and kidney function, glucose metabolism and lipid metabolism of 11 922 participants who underwent physical examination at the Health Management Center of the Second Xiangya Hospital of Central South University from January 2019 to December 2019 were collected. Clinical characteristics and independent factors of patients with discordance between HbA1c and FPG were evaluated and analyzed. The prevalence of HbA1c-defined diabetes and prediabetes (respectively 8.13%, 34.79%) were significantly higher than that in FPG-defined diabetes and prediabetes (respectively 4.70%, 8.97%) (χ²=2 635.940;P<0.001). The prevalence of inconsistence between HbA1c and FPG was 35.65% and increased with increasing age. This inconsistence mainly occurred in population with HbA1c:5.7%-6.0% and FPG<5.6 mmol/L, followed by population with HbA1c:6.1%-6.4% and FPG<5.6 mmol/L. The risk factors of inconsistency included advanced age, overweight or obesity, hypoalbuminemia, dyslipidemia and hyperuricemia. Among these special participants, compared with participants under 45 years old, participants with over 45 years of age (OR=3.525, 95%CI: 3.216-3.863, P<0.001) were more likely to have inconsistence between HbA1c and FPG; and overweight participants (OR=1.474, 95%CI: 1.341-1.620, P<0.001) or obese participants (OR=1.856, 95%CI: 1.633-2.110, P<0.001) are prone to have the inconsistence than those with normal weight.

Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to &lt;10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to &lt;10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to &lt;10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p&lt;0,0001), 94% (p=0,034); post-ASCT 86% (p&lt;0,0001), 90% (p=0,022); post-Cons 89% (p&lt;0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

Real-Life Head-to-Head Comparison of Performance of Two High-Throughput Automated Assays for the Detection of SARS-CoV-2 RNA in Nasopharyngeal Swabs: The Alinity m and cobas 6800 SARS-CoV-2 Assays

The Alinity m (Abbott Molecular, Des Plaines, IL) automated molecular analyzer allows continuous loading of samples and sample-to-result molecular detection of several microorganisms. The detection of SARS-CoV-2 by the Alinity m was compared with that of the cobas 6800 (Roche Molecular Systems, Branchburg, NJ; standard comparator) in a manufacturer-independent clinical evaluation on 2157 consecutive nasopharyngeal swab samples. Valid initial results on Alinity m and cobas 6800 were obtained from 2129 (98.7%) and 2157 (100%) samples, respectively. The overall percent agreement (95% CI) was 98.3% (2092/2129 [97.6%–98.7%]); positive percent agreement, 100% (961/961 [99.6%–100%]); negative percent agreement, 96.8% (1131/1168 [95.7%–97.7%]); and high κ value, 0.965 (0.954–0.976). There were 37 discordant results on Alinity m and, based on discordant analyses, including previous and/or follow-up PCR results, 22 could be considered analytically true positive with high probability. Due to a lack of additional information and an inability to perform repeated/further testing, the status of the remaining 15 discordant results remained unresolved. The throughput of the two analyzers was compared using testing on 564 samples in parallel across two 8-hour shifts in clinical practice. The turnaround times were compared using processing of 94 routine samples in parallel on each working day for 5 consecutive days. The two analyzers showed similar performance, with certain differences that have potential importance in some laboratory settings.

Effects of age on psychosocial working conditions and future labour market marginalisation: a cohort study of 56,867 Swedish twins

PurposePrevious studies have reported an elevated risk of sickness absence (SA) and disability pension (DP) due to adverse psychosocial working conditions, yet the influence of age and familial factors on the associations have not been examined. We aimed to investigate associations between psychosocial working conditions and labour market marginalisation (LMM) in terms of unemployment, SA and DP adjusting for familial confounding and possible differences in these associations with different age groups and different unemployment and sick leave days.MethodsAll twins living in Sweden in 2001, aged 16–64 years and not on old-age pension or DP were included (n = 56,867). The twins were followed from 2002 to 2016 regarding unemployment, SA and DP. Cox proportional hazards regression models were performed for the whole sample, and for discordant twin pairs, in five age groups.ResultsEach one-unit increase in job demands and job control was associated with a lower risk of unemployment, SA and DP in all age groups. Moreover, each one-unit increase in social support was associated with an increased risk of 1–30 days unemployment in individuals older than 45 years and SA and DP. Social support decreased the risk of unemployment longer than 365 days in age groups 16–25 and 36–45 years. In the discordant twin pair analyses, the estimates attenuated towards statistical non-significance.ConclusionEven though familial factors seem to influence the associations between psychosocial working conditions and LMM, improving psychosocial working conditions by for example promoting high job control and social support at workplace may reduce the risk of future short- and long-term LMM in all age groups.

On the treatment of discordant detrital zircon U–Pb data

Abstract. Zircon U–Pb geochronology is a staple of crustal evolution studies and sedimentary provenance analysis. Constructing (detrital) U–Pb age spectra is straightforward for concordant 206Pb/238U and 207Pb/206Pb compositions. But unfortunately, many U–Pb datasets contain a significant proportion of discordant analyses. This paper investigates two decisions that must be made when analysing such discordant U–Pb data. First, the analyst must choose whether to use the 206Pb/238U or the 207Pb/206Pb date. The 206Pb/238U method is more precise for young samples, whereas the 207Pb/206Pb method is better suited for old samples. However there is no agreement which “cutoff” should be used to switch between the two. This subjective decision can be avoided by using single-grain concordia ages. These represent a kind of weighted mean between the 206Pb/238U and 207Pb/206Pb methods, which offers better precision than either of the latter two methods. A second subjective decision is how to define the discordance cutoff between “good” and “bad” data. Discordance is usually defined as (1) the relative age difference between the 206Pb/238U and 207Pb/206Pb dates. However, this paper shows that several other definitions are possible as well, including (2) the absolute age difference; (3) the common-Pb fraction according to the Stacey–Kramers mantle evolution model; (4) the p value of concordance; (5) the perpendicular log ratio (or “Aitchison”) distance to the concordia line; and (6) the log ratio distance to the maximum likelihood composition on the concordia line. Applying these six discordance filters to a 70 869-grain dataset of zircon U–Pb compositions reveals that (i) the relative age discordance filter tends to suppress the young age components in U–Pb age spectra, whilst inflating the older age components; (ii) the Stacey–Kramers discordance filter is more likely to reject old grains and less likely to reject young ones; (iii) the p-value-based discordance filter has the undesirable effect of biasing the results towards the least precise measurements; (iv) the log-ratio-based discordance filters are strictest for Proterozoic grains and more lenient for Phanerozoic and Archaean age components; (v) of all the methods, the log ratio distance to the concordia composition produces the best results, in the sense that it produces age spectra that most closely match those of the unfiltered data: it sharpens age spectra but does not change their shape. The popular relative age definition fares the worst according to this criterion. All the methods presented in this paper have been implemented in the IsoplotR toolbox for geochronology.

Update on apolipoprotein B.

The 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines concluded that apolipoprotein B (apoB) was a more accurate measure of cardiovascular risk and a better guide to the adequacy of lipid lowering than low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (HDL-C). Also, they stated that apoB can be measured more accurately than LDL-C or non-HDL-C. This strong endorsement of the central role of apoB contrasts with the limited endorsement of apoB by the 2018 American College of Cardiology/American Heart Association Multisociety Guidelines. Nevertheless, both retained LDL-C as the primary metric to guide statin/ezetimibe/Proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy. This essay will review the most important recent advances in knowledge about apoB with particular emphasis on the results of Mendelian randomization studies and a new discordance analysis in subjects on statin therapy. We will also lay out why using LDL-C to guide the adequacy of lipid lowering therapy represents an interpretive error of the results of the statin/ezetimibe/PCSK9 inhibitor randomized clinical trials and therefore why apoB should be the primary metric to guide statin/ezetimibe/PCSK9 therapy. There is now a robust body of evidence demonstrating the superiority of apoB over LDL-C and non-HDL-C as a clinical marker of cardiovascular risk. LDL-C is not the appropriate marker to assess the benefits of statin/ezetimibe/PCSK9 therapy.

A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [18F]flutemetamol amyloid PET images

Background[18F]flutemetamol PET scanning provides information on brain amyloid load and has been approved for routine clinical use based upon visual interpretation as either negative (equating to none or sparse amyloid plaques) or amyloid positive (equating to moderate or frequent plaques). Quantitation is however fundamental to the practice of nuclear medicine and hence can be used to supplement amyloid reading methodology especially in unclear cases.MethodsA total of 2770 [18F]flutemetamol images were collected from 3 clinical studies and 6 research cohorts with available visual reading of [18F]flutemetamol and quantitative analysis of images. These were assessed further to examine both the discordance and concordance between visual and quantitative imaging primarily using thresholds robustly established using pathology as the standard of truth. Scans covered a wide range of cases (i.e. from cognitively unimpaired subjects to patients attending the memory clinics). Methods of quantifying amyloid ranged from using CE/510K cleared marked software (e.g. CortexID, Brass), to other research-based methods (e.g. PMOD, CapAIBL). Additionally, the clinical follow-up of two types of discordance between visual and quantitation (V+Q- and V-Q+) was examined with competing risk regression analysis to assess possible differences in prediction for progression to Alzheimer’s disease (AD) and other diagnoses (OD).ResultsWeighted mean concordance between visual and quantitation using the autopsy-derived threshold was 94% using pons as the reference region. Concordance from a sensitivity analysis which assessed the maximum agreement for each cohort using a range of cut-off values was also estimated at approximately 96% (weighted mean). Agreement was generally higher in clinical cases compared to research cases. V-Q+ discordant cases were 11% more likely to progress to AD than V+Q- for the SUVr with pons as reference region.ConclusionsQuantitation of amyloid PET shows a high agreement vs binary visual reading and also allows for a continuous measure that, in conjunction with possible discordant analysis, could be used in the future to identify possible earlier pathological deposition as well as monitor disease progression and treatment effectiveness.

Onset of Preclinical Alzheimer Disease in Monozygotic Twins.

ObjectiveThe present work was undertaken to study the genetic contribution to the start of Alzheimer's disease (AD) with amyloid and tau biomarkers in cognitively intact older identical twins.MethodsWe studied in 96 monozygotic twin‐pairs relationships between amyloid‐beta (Aβ) aggregation as measured by the Aβ1–42/1–40 ratio in cerebrospinal fluid (CSF; n = 126) and positron emission tomography (PET, n = 194), and CSF markers for Aβ production (beta‐secretase 1, Aβ1–40, and Aβ1–38) and CSF tau. Associations among markers were tested with generalized estimating equations including a random effect for twin status, adjusted for age, gender, and apolipoprotein E ε4 genotype. We used twin analyses to determine relative contributions of genetic and/or environmental factors to AD pathophysiological processes.ResultsTwenty‐seven individuals (14%) had an abnormal amyloid PET, and 14 twin‐pairs (15%) showed discordant amyloid PET scans. Within twin‐pairs, Aβ production markers and total‐tau (t‐tau) levels strongly correlated (r range = 0.73–0.86, all p < 0.0001), and Aβ aggregation markers and 181‐phosphorylated‐tau (p‐tau) levels correlated moderately strongly (r range = 0.50–0.64, all p < 0.0001). Cross‐twin cross‐trait analysis showed that Aβ1–38 in one twin correlated with Aβ1–42/1–40 ratios, and t‐tau and p‐tau levels in their cotwins (r range = −0.28 to 0.58, all p < .007). Within‐pair differences in Aβ production markers related to differences in tau levels (r range = 0.49–0.61, all p < 0.0001). Twin discordance analyses suggest that Aβ production and tau levels show coordinated increases in very early AD.InterpretationOur results suggest a substantial genetic/shared environmental background contributes to both Aβ and tau increases, suggesting that modulation of environmental risk factors may aid in delaying the onset of AD pathophysiological processes. ANN NEUROL 2021;89:987–1000

Apolipoprotein B and Non-HDL Cholesterol Better Reflect Residual Risk Than LDL Cholesterol in Statin-Treated Patients

BackgroundIn cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non–high-density lipoprotein (non-HDL) cholesterol are secondary targets. ObjectivesThis study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction. MethodsIn total, 13,015 statin-treated patients from the Copenhagen General Population Study were included with 8 years median follow-up. Cox regressions among apoB, non-HDL cholesterol, and LDL cholesterol, respectively, and all-cause mortality or myocardial infarction were examined on continuous scales by restricted cubic splines and by categories of concordant and discordant values defined by medians. ResultsHigh apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, whereas no such associations were found for high LDL cholesterol. Compared with concordant values below medians, discordant apoB above the median with LDL cholesterol below yielded hazard ratios of 1.21 (95% confidence interval [CI]: 1.07 to 1.36) for all-cause mortality and 1.49 (95% CI: 1.15 to 1.92) for myocardial infarction. Corresponding values for high non-HDL cholesterol with low LDL cholesterol were 1.18 (95% CI: 1.02 to 1.36) and 1.78 (95% CI: 1.35 to 2.34). In contrast, discordant high LDL cholesterol with low apoB or non-HDL cholesterol was not associated with increased risk of all-cause mortality or myocardial infarction. Also, discordant high apoB with low non-HDL cholesterol yielded hazard ratios of 1.21 (95% CI: 1.03 to 1.41) for all-cause mortality and of 0.93 (95% CI: 0.62 to 1.40) for myocardial infarction. Furthermore, dual discordant apoB and non-HDL cholesterol above the medians with LDL cholesterol below presented hazard ratios of 1.23 (95% CI: 1.07 to 1.43) for all-cause mortality and 1.82 (95% CI: 1.37 to 2.42) for myocardial infarction. ConclusionsIn statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL cholesterol or non-HDL cholesterol, and apoB in addition is a more accurate marker of risk of myocardial infarction than LDL cholesterol.

Small Dense Low-Density Lipoprotein Cholesterol Is the Most Atherogenic Lipoprotein Parameter in the Prospective Framingham Offspring Study.

BackgroundElevated plasma levels of direct low‐density lipoprotein cholesterol (LDL‐C), small dense LDL‐C (sdLDL‐C), low‐density lipoprotein (LDL) triglycerides, triglycerides, triglyceride‐rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and lipoprotein(a) have all been associated with incident atherosclerotic cardiovascular disease (ASCVD). Our goal was to assess which parameters were most strongly associated with ASCVD risk.Methods and ResultsPlasma total cholesterol, triglycerides, high‐density lipoprotein cholesterol, direct LDL‐C, sdLDL‐C, LDL triglycerides, remnant lipoprotein particle cholesterol, triglyceride‐rich lipoprotein cholesterol, and lipoprotein(a) were measured using standardized automated analysis (coefficients of variation, <5.0%) in samples from 3094 fasting subjects free of ASCVD. Of these subjects, 20.2% developed ASCVD over 16 years. On univariate analysis, all ASCVD risk factors were significantly associated with incident ASCVD, as well as the following specialized lipoprotein parameters: sdLDL‐C, LDL triglycerides, triglycerides, triglyceride‐rich lipoprotein cholesterol, remnant lipoprotein particle cholesterol, and direct LDL‐C. Only sdLDL‐C, direct LDL‐C, and lipoprotein(a) were significant on multivariate analysis and net reclassification after adjustment for standard risk factors (age, sex, hypertension, diabetes mellitus, smoking, total cholesterol, and high‐density lipoprotein cholesterol). Using the pooled cohort equation, many specialized lipoprotein parameters individually added significant information, but no parameter added significant information once sdLDL‐C (hazard ratio, 1.42; P<0.0001) was in the model. These results for sdLDL‐C were confirmed by adjusted discordance analysis versus calculated non–high‐density lipoprotein cholesterol, in contrast to LDL triglycerides.ConclusionssdLDL‐C, direct LDL‐C, and lipoprotein(a) all contributed significantly to ASCVD risk on multivariate analysis, but no parameter added significant risk information to the pooled cohort equation once sdLDL‐C was in the model. Our data indicate that small dense LDL is the most atherogenic lipoprotein parameter.

False negative rate of COVID-19 PCR testing: a discordant testing analysis

BackgroundCOVID-19 is diagnosed via detection of SARS-CoV-2 RNA using real time reverse-transcriptase polymerase chain reaction (rtRT-PCR). Performance of many SARS-CoV-2 rtRT-PCR assays is not entirely known due to the lack of a gold standard. We sought to evaluate the false negative rate (FNR) and sensitivity of our laboratory-developed SARS-CoV-2 rtRT-PCR targeting the envelope (E) and RNA-dependent RNA-polymerase (RdRp) genes.MethodsSARS-CoV-2 rtRT-PCR results at the Public Health Laboratory (Alberta, Canada) from January 21 to April 18, 2020 were reviewed to identify patients with an initial negative rtRT-PCR followed by a positive result on repeat testing within 14 days (defined as discordant results). Negative samples from these discordant specimens were re-tested using three alternate rtRT-PCR assays (targeting the E gene and N1/N2 regions of the nucleocapsid genes) to assess for false negative (FN) results.ResultsDuring the time period specified, 95,919 patients (100,001 samples) were tested for SARS-CoV-2. Of these, 49 patients were found to have discordant results including 49 positive and 52 negative swabs. Repeat testing of 52 negative swabs found five FNs (from five separate patients). Assuming 100% specificity of the diagnostic assay, the FNR and sensitivity in this group of patients with discordant testing was 9.3% (95% CI 1.5–17.0%) and 90.7% (95% CI 82.6–98.9%) respectively.ConclusionsStudies to understand the FNR of routinely used assays are important to confirm adequate clinical performance. In this study, most FN results were due to low amounts of SARS-CoV-2 virus concentrations in patients with multiple specimens collected during different stages of infection. Post-test clinical evaluation of each patient is advised to ensure that rtRT-PCR results are not the only factor in excluding COVID-19.

Genetic drivers of longevity provide protection against Alzheimer's disease pathology

AbstractBackgroundGenome‐wide association studies (GWAS) have consistently found human longevity correlations within the APOE gene cluster (APOE, APOC1, TOMM40, PVRL2). Many variants in this cluster show inverse effects between longevity and Alzheimer’s disease (AD). This suggests genetic pleiotropy between AD and longevity, e.g., the APOE ε2 allele is associated with both protection from AD and increased longevity. Recent evidence supports the idea that certain aged individuals do not have significant AD pathology, exhibiting AD resistance. Here we sought to determine whether a genetic signal of AD resistance could be identified by leveraging previous GWAS of longevity and AD pathology.MethodWe used a large meta‐analysis of longevity, defined as reaching the 90th age percentile for a birth cohort compared to those who reach the 60th. Following p‐value informed LD‐clumping (r2 ≥ 0.1), we used random‐effects regression to meta‐analyze three GWAS on AD phenotypes: cerebrospinal fluid levels of amyloid, and phosphorylated tau, as well as amyloid PET imaging. Subsequent methods are shown in Figure 1 and involved mapping variants to genes and determining gene scores and pathway enrichment using PASCAL.ResultsVariants showing discordant effects between AD pathology and longevity (increased pathology/decreased longevity or decreased pathology/increased longevity) included APOE and others across the genome. The top Reactome pathways (p &lt; 0.05) included those involved in axon growth and guidance (Signal transduction and recycling by L1, signalling of NGF, Neurotrophin signalling), cell survival and apoptosis (MAPK pathway, ERK/MAPK targets, NFKB/MAPK activation by TLR4), lipid metabolism (chylomicron‐mediated and HDL‐mediated lipid transport), and the immune system (innate and adaptive).ConclusionSignificant pleiotropy exists between longevity and AD pathology, implying that focus on discordant effects may yield novel insights relevant to AD resistance. Ongoing work seeks to map results from our discordance analysis to an AD‐specific transcriptional regulatory network created from the Harvard Brain Tissue Resource Center data, with hubs of known transcription factors. This will allow identification of functional modules via eQTL enrichment, will help to further characterize these effects, and may prove useful for downstream drug repurposing analyses.

Apolipoprotein B: the Rosetta Stone of lipidology.

This review summarizes the evidence that apolipoprotein B (apoB) integrates the conventional lipid markers - total cholesterol, triglycerides, LDL-cholesterol, and non-HDL-cholesterol - into a single index that accurately and simply quantitates the atherogenic risk due to the apoB lipoprotein particles. Marked hypertriglyceridemia remains the essential signal for hyperchylomicronemia and potential pancreatitis. However, with the exception of Lp(a) and the abnormal cholesterol-enriched remnant particles that are the hallmark of type III hyperlipoproteinemia, recent evidence from discordance analyses and Mendelian randomization indicate that apoB integrates the risk due to the atherogenic lipoprotein particles because all LDL particles are, within the limits of our ability to measure any differences, equally atherogenic and all, except the largest VLDL particles are, within the limits of our ability to measure any differences, equally atherogenic. Measuring apoB as well as the conventional lipids is essential for accurate diagnosis. For almost all follow-up, however, apoB is all that need be measured. ApoB is the Rosetta Stone of lipidology because dyslipoproteinemia cannot be understood unless apoB is measured.

Abstract 14845: Remnant Cholesterol and Incident Atherosclerotic Cardiovascular Disease: A Pooled Cohort Primary Prevention Study

Introduction: Emerging evidence suggests that remnant cholesterol (RC) promotes future atherosclerotic cardiovascular disease (ASCVD) events. Our aim was to estimate the risk associated with RC beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB). Hypothesis: RC provides incremental prognostic information regarding incident ASCVD, independent of LDL-C and apoB. Methods: We pooled data from 17,532 individuals from Atherosclerosis Risk in Communities study (n=9,748), Multi-Ethnic Study of Atherosclerosis (n=3,049) and Coronary Artery Risk Development in Young Adults (n=4,735), who were ASCVD-free at baseline and had measurements of lipids, apoB and apolipoprotein A1. RC was calculated as non-high-density cholesterol (non-HDL-C) minus LDL-C estimated by the Martin/Hopkins equation. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in discordant/concordant groups of RC and LDL-C across median cutpoints and cutpoints of percentile equivalence to LDL-C targets (70 and 100 mg/dL). Results: Mean age of participants was 52.3±17.9 years, 56.7% women and 34% black. There were 2,143 ASCVD events over median follow-up of 18.7 years. After multivariable adjustment including apoB and HDL-C, logRC was associated with higher ASCVD risk [HR 1.42, 95% CI (1.23-1.63)]. In discordance analyses, the high RC and low LDL-C group (≥/&lt;median) was associated with increased ASCVD risk compared to the low/low concordant group [1.17, (1.01-1.35)] but the low RC and high LDL-C group was not. Similar results were shown when examining discordance across lower cutpoints. Conclusion: In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors and LDL-C and apoB levels. RC assessment and management in primary prevention, beyond LDL-C and apoB, is useful and requires further scrutiny.

TIP_finder: An HPC Software to Detect Transposable Element Insertion Polymorphisms in Large Genomic Datasets.

Transposable elements (TEs) are non-static genomic units capable of moving indistinctly from one chromosomal location to another. Their insertion polymorphisms may cause beneficial mutations, such as the creation of new gene function, or deleterious in eukaryotes, e.g., different types of cancer in humans. A particular type of TE called LTR-retrotransposons comprises almost 8% of the human genome. Among LTR retrotransposons, human endogenous retroviruses (HERVs) bear structural and functional similarities to retroviruses. Several tools allow the detection of transposon insertion polymorphisms (TIPs) but fail to efficiently analyze large genomes or large datasets. Here, we developed a computational tool, named TIP_finder, able to detect mobile element insertions in very large genomes, through high-performance computing (HPC) and parallel programming, using the inference of discordant read pair analysis. TIP_finder inputs are (i) short pair reads such as those obtained by Illumina, (ii) a chromosome-level reference genome sequence, and (iii) a database of consensus TE sequences. The HPC strategy we propose adds scalability and provides a useful tool to analyze huge genomic datasets in a decent running time. TIP_finder accelerates the detection of transposon insertion polymorphisms (TIPs) by up to 55 times in breast cancer datasets and 46 times in cancer-free datasets compared to the fastest available algorithms. TIP_finder applies a validated strategy to find TIPs, accelerates the process through HPC, and addresses the issues of runtime for large-scale analyses in the post-genomic era.