All Publications


  • Finding missed cases of familial hypercholesterolemia in health systems using machine learning. NPJ digital medicine Banda, J. M., Sarraju, A., Abbasi, F., Parizo, J., Pariani, M., Ison, H., Briskin, E., Wand, H., Dubois, S., Jung, K., Myers, S. A., Rader, D. J., Leader, J. B., Murray, M. F., Myers, K. D., Wilemon, K., Shah, N. H., Knowles, J. W. 2019; 2: 23

    Abstract

    Familial hypercholesterolemia (FH) is an underdiagnosed dominant genetic condition affecting approximately 0.4% of the population and has up to a 20-fold increased risk of coronary artery disease if untreated. Simple screening strategies have false positive rates greater than 95%. As part of the FH Foundation's FIND FH initiative, we developed a classifier to identify potential FH patients using electronic health record (EHR) data at Stanford Health Care. We trained a random forest classifier using data from known patients (n = 197) and matched non-cases (n = 6590). Our classifier obtained a positive predictive value (PPV) of 0.88 and sensitivity of 0.75 on a held-out test-set. We evaluated the accuracy of the classifier's predictions by chart review of 100 patients at risk of FH not included in the original dataset. The classifier correctly flagged 84% of patients at the highest probability threshold, with decreasing performance as the threshold lowers. In external validation on 466 FH patients (236 with genetically proven FH) and 5000 matched non-cases from the Geisinger Healthcare System our FH classifier achieved a PPV of 0.85. Our EHR-derived FH classifier is effective in finding candidate patients for further FH screening. Such machine learning guided strategies can lead to effective identification of the highest risk patients for enhanced management strategies.

    View details for DOI 10.1038/s41746-019-0101-5

    View details for PubMedID 31304370

    View details for PubMedCentralID PMC6550268

  • Genetic Testing and Risk Scores: Impact on Familial Hypercholesterolemia. Frontiers in cardiovascular medicine Sarraju, A., Knowles, J. W. 2019; 6: 5

    Abstract

    Familial Hypercholesterolemia (FH) is an inherited lipid disorder affecting 1 in 220 individuals resulting in highly elevated low-density lipoprotein levels and risk of premature coronary disease. Pathogenic variants causing FH typically involve the LDL receptor (LDLR), apolipoprotein B-100 (APOB), and proprotein convertase subtulisin/kexin type 9 genes (PCSK9) and if identified convey a risk of early onset coronary artery disease (ASCVD) of 3- to 10-fold vs. the general population depending on the severity of the mutation. Identification of monogenic FH within a family has implications for family-based testing (cascade screening), risk stratification, and potentially management, and it has now been recommended that such testing be offered to all potential FH patients. Recently, robust genome wide association studies (GWAS) have led to the recognition that the accumulation of common, small effect alleles affecting many LDL-c raising genes can result in a clinical phenotype largely indistinguishable from monogenic FH (i.e., a risk of early onset ASCVD of ~3-fold) in those at the extreme tail of the distribution for these alleles (i.e., the top 8% of the population for a polygenic risk score). The incorporation of these genetic risk scores into clinical practice for non-FH patients may improve risk stratification but is not yet widely performed due to a less robust evidence base for utility. Here, we review the current status of FH genetic testing, potential future applications as well as challenges and pitfalls.

    View details for PubMedID 30761309

  • Dietary Patterns and Long-Term Survival: a Retrospective Study of Healthy Primary Care Patients. The American journal of medicine Shah, N. S., Leonard, D., Finley, C. E., Rodriguez, F., Sarraju, A., Barlow, C. E., DeFina, L. F., Willis, B. L., Haskell, W. L., Maron, D. J. 2017

    Abstract

    Dietary patterns are related to mortality in selected populations with comorbidities. We studied whether dietary patterns are associated with long-term survival in a middle-aged, healthy population.In this observational cohort study at the Cooper Clinic preventive medicine center (Dallas, Texas), a volunteer sample of 11,376 men and women with no history of myocardial infarction or stroke completed a baseline dietary assessment between 1987-1999 and were observed for an average of 18 years. Proportional hazard regressions, including a tree-augmented model, were used to assess the association of the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, Mediterranean dietary pattern, and individual dietary components with mortality. The primary outcome was death from all causes. The secondary outcome was death from cardiovascular disease.Mean baseline age was 47 years. Each quintile increase in the DASH diet score was associated with a 6% lower adjusted risk for all-cause mortality (P<0.02). The Mediterranean diet was not independently associated with all-cause or cardiovascular mortality. Solid fats and added sugars were the most predictive of mortality. Individuals who consumed >34% of their daily calories as solid fats had the highest risk for all-cause mortality.The DASH dietary pattern was associated with significantly lower all-cause mortality over nearly two decades of follow-up in a middle-aged, generally healthy population. Added solid fat and added sugar intake were the most predictive of all-cause mortality. These results suggest that promotion of a healthy dietary pattern should begin in middle age, before the development of comorbid risk factors.

    View details for PubMedID 28860032

  • Is ACS in Young Patients a "Canary in the Coal Mine" for Familial Hypercholesterolemia? Journal of the American College of Cardiology Knowles, J. W., Sarraju, A. 2017; 70 (14): 1741–43

    View details for PubMedID 28958331

  • Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials). American journal of cardiology Kohli, P., Knowles, J. W., Sarraju, A., Waters, D. D., Reaven, G. 2016; 118 (9): 1275-1281

    Abstract

    The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m(2)), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m(2) <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.

    View details for DOI 10.1016/j.amjcard.2016.07.054

    View details for PubMedID 27614854

  • Novel Therapies for Familial Hypercholesterolemia. Current treatment options in cardiovascular medicine Parizo, J., Sarraju, A., Knowles, J. W. 2016; 18 (11): 64-?

    Abstract

    Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added. Finally, LDL-C apheresis can be considered in patients with LDL-C >300 mg/dL (or >200 mg/dL with significant CAD, although now approved for LDL-C as low as 160 mg/dL with CAD). Due to the early, severe LDL-C elevation in HoFH patients, concerning natural history, rarity of the condition, and nuances of treatment, all HoFH patients should be treated at a pediatric or adult center with HoFH experience. LDL-C apheresis should be considered as early as 5 years of age. However, apheresis availability and tolerability is limited and pharmacotherapy is required. Generally, the AHA algorithm with reference to the European Atherosclerosis Society Consensus Panel recommendations is reasonable with all patients initiated on high-dose, high-potency statin, ezetimibe, and bile acid-binding resins. In most, additional LDL-C lowering is required with PCSK9 inhibitors and/or lomitapide or mipomersen. Liver transplantation can also be considered at experienced centers as a last resort.

    View details for DOI 10.1007/s11936-016-0486-2

    View details for PubMedID 27620638

  • Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists. Current atherosclerosis reports Sarraju, A., Kim, S. H., Knowles, J. W. 2016; 18 (2): 7-?

    Abstract

    Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.

    View details for DOI 10.1007/s11883-016-0558-5

    View details for PubMedID 26782825

  • Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors PLOS ONE Brudner, M., Karpel, M., Lear, C., Chen, L., Yantosca, L. M., Scully, C., Sarraju, A., Sokolovska, A., Zariffard, M. R., Eisen, D. P., Mungall, B. A., Kotton, D. N., Omari, A., Huang, I., Farzan, M., Takahashi, K., Stuart, L., Stahl, G. L., Ezekowitz, A. B., Spear, G. T., Olinger, G. G., Schmidt, E. V., Michelow, I. C. 2013; 8 (4)

    Abstract

    Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.

    View details for DOI 10.1371/journal.pone.0060838

    View details for Web of Science ID 000317717300151

    View details for PubMedID 23573288

  • Tailoring Encodable Lanthanide-Binding Tags as MRI Contrast Agents CHEMBIOCHEM Daughtry, K. D., Martin, L. J., Sarraju, A., Imperiali, B., Allen, K. N. 2012; 13 (17): 2567-2574

    Abstract

    Lanthanide-binding tags (LBTs), peptide-based coexpression tags with high affinity for lanthanide ions, have previously been applied as luminescent probes to provide phasing for structure determination in X-ray crystallography and to provide restraints for structural refinement and distance information in NMR. The native affinity of LBTs for Gd(3+) indicates their potential as the basis for engineering of peptide-based MRI agents. However, the lanthanide coordination state that enhances luminescence and affords tightest binding would not be ideal for applications of LBTs as contrast agents, due to the exclusion of water from the inner coordination sphere. Herein, we use structurally defined LBTs as the starting point for re-engineering the first coordination shell of the lanthanide ion to provide for high contrast through direct coordination of water to Gd(3+) (resulting in the single LBT peptide, m-sLBT). The effectiveness of LBTs as MRI contrast agents was examined in vitro through measurement of binding affinity and proton relaxivity. For imaging applications that require targeted observation, fusion to specific protein partners is desirable. However, a fusion protein comprising a concatenated double LBT (dLBT) as an N-terminal tag for the model protein ubiquitin had reduced relaxivity compared with the free dLBT peptide. This limitation was overcome by the use of a construct based on the m-sLBT sequence (q-dLBT-ubiquitin). The structural basis for the enhanced contrast was examined by comparison of the X-ray crystal structure of xq-dLBT-ubiquitin (wherein two tryptophan residues are replaced with serine), to that of dLBT-ubiquitin. The structure shows that the backbone conformational dynamics of the MRI variant may allow enhanced water exchange. This engineered LBT represents a first step in expanding the current base of specificity-targeted agents available.

    View details for DOI 10.1002/cbic.201200448

    View details for Web of Science ID 000311245800014

    View details for PubMedID 23150430