Validation of a Deep Learning Algorithm for Continuous, Real-Time Detection of Atrial Fibrillation Using a Wrist-Worn Device in an Ambulatory Environment.

BACKGROUND: Wearable devices may be useful for identification, quantification and characterization, and management of atrial fibrillation (AF). To date, consumer wrist-worn devices for AF detection using photoplethysmography-based algorithms perform only periodic checks when the user is stationary and are US Food and Drug Administration cleared for prediagnostic uses without intended use for clinical decision-making. There is an unmet need for medical-grade diagnostic wrist-worn devices that provide long-term, continuous AF monitoring. METHODS AND RESULTS: We evaluated the performance of a wrist-worn device with lead-I ECG and continuous photoplethysmography (Verily Study Watch) and photoplethysmography-based convolutional neural network for AF detection and burden estimation in a prospective multicenter study that enrolled 117 patients with paroxysmal AF. A 14-day continuous ECG monitor (Zio XT) served as the reference device to evaluate algorithm sensitivity and specificity for detection of AF in 15-minute intervals. A total of 91 857 intervals were contributed by 111 subjects with evaluable reference and test data (18.3 h/d median watch wear time). The watch was 96.1% sensitive (95% CI, 92.7%-98.0%) and 98.1% specific (95% CI, 97.2%-99.1%) for interval-level AF detection. Photoplethysmography-derived AF burden estimation was highly correlated with the reference device burden (R2=0.986) with a mean difference of 0.8% (95% limits of agreement, -6.6% to 8.2%). CONCLUSIONS: Continuous monitoring using a photoplethysmography-based convolutional neural network incorporated in a wrist-worn device has clinical-grade performance for AF detection and burden estimation. These findings suggest that monitoring can be performed with wrist-worn wearables for diagnosis and clinical management of AF. REGISTRATION INFORMATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04546763.

Are minor alleles more likely to be risk alleles?

BACKGROUND: Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele. METHODS: Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion. RESULTS: Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs < 0.1). Our computer simulations revealed that > 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (< 0.1) were much larger than the expected ratios of GWAS's power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus. CONCLUSIONS: Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS's power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.

Genetic analysis in a patient with nine primary malignant neoplasms: a rare case of Li-Fraumeni syndrome.

To identify rare mutations and retrospectively estimate the cancer risk of a 45-year old female patient diagnosed with Li-Fraumeni syndrome (LFS), who developed nine primary malignant neoplasms in a period of 38 years, we conducted next-generation sequencing in this patient. Whole-genome and whole-exome sequencing were performed in DNA of whole blood obtained a year prior to the diagnosis of acute myeloid leukemia (AML) and at the time of diagnosis of AML, respectively. We analyzed rare mutations in cancer susceptibility genes using a candidate strategy and estimated cancer risk using the Risk-O-Gram algorithm. We found rare mutations in cancer susceptibility genes associated with an increased hereditary cancer risk in the patient. Notably, the number of mutated genes in p53 signaling pathway was significantly higher than expected (p=0.02). However, the phenotype of multiple malignant neoplasms of the studied patient was unlikely to be caused by accumulation of common cancer risk alleles. In conclusion, we established the mutation profile in a rare case of Li-Fraumeni syndrome, illustrating that the rare mutations rather than the cumulative of common risk alleles leading to an increased cancer risk in the patient.

Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing.

Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10-12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01×10(-5)) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10(-4)) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10(-4)) and non-RNF213 founder mutation (P = 1.51×10(-3)) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10(-4)) and non-RNF213 founder mutation cases (P = 5.31×10(-5)). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis.

Achieving high-sensitivity for clinical applications using augmented exome sequencing.

BACKGROUND: Whole exome sequencing is increasingly used for the clinical evaluation of genetic disease, yet the variation of coverage and sensitivity over medically relevant parts of the genome remains poorly understood. Several sequencing-based assays continue to provide coverage that is inadequate for clinical assessment. METHODS: Using sequence data obtained from the NA12878 reference sample and pre-defined lists of medically-relevant protein-coding and noncoding sequences, we compared the breadth and depth of coverage obtained among four commercial exome capture platforms and whole genome sequencing. In addition, we evaluated the performance of an augmented exome strategy, ACE, that extends coverage in medically relevant regions and enhances coverage in areas that are challenging to sequence. Leveraging reference call-sets, we also examined the effects of improved coverage on variant detection sensitivity. RESULTS: We observed coverage shortfalls with each of the conventional exome-capture and whole-genome platforms across several medically interpretable genes. These gaps included areas of the genome required for reporting recently established secondary findings (ACMG) and known disease-associated loci. The augmented exome strategy recovered many of these gaps, resulting in improved coverage in these areas. At clinically-relevant coverage levels (100 % bases covered at ≥20×), ACE improved coverage among genes in the medically interpretable genome (>90 % covered relative to 10-78 % with other platforms), the set of ACMG secondary finding genes (91 % covered relative to 4-75 % with other platforms) and a subset of variants known to be associated with human disease (99 % covered relative to 52-95 % with other platforms). Improved coverage translated into improvements in sensitivity, with ACE variant detection sensitivities (>97.5 % SNVs, >92.5 % InDels) exceeding that observed with conventional whole-exome and whole-genome platforms. CONCLUSIONS: Clinicians should consider analytical performance when making clinical assessments, given that even a few missed variants can lead to reporting false negative results. An augmented exome strategy provides a level of coverage not achievable with other platforms, thus addressing concerns regarding the lack of sensitivity in clinically important regions. In clinical applications where comprehensive coverage of medically interpretable areas of the genome requires higher localized sequencing depth, an augmented exome approach offers both cost and performance advantages over other sequencing-based tests.

Clinically significant novel biomarkers for prediction of first ever myocardial infarction: the Tromsø Study.

BACKGROUND: Identification of individuals with high risk for first-ever myocardial infarction (MI) can be improved. The objectives of the study were to survey multiple protein biomarkers for association with the 10-year risk of incident MI and identify a clinically significant risk model that adds information to current common risk models. METHODS AND RESULTS: We used an immunoassay platform that uses a sensitive, sample-efficient molecular counting technology to measure 51 proteins in samples from the fourth survey (1994) in the Tromsø Study, a longitudinal study of men and women in Tromsø, Norway. A case control design was used with 419 first-ever MI cases (169 females/250 males) and 398 controls (244 females/154 males). Of the proteins measured, 17 were predictors of MI when considered individually after adjustment for traditional risk factors either in men, women, or both. The 6 biomarkers adjusted for traditional risk factors that were selected in a multivariable model (odds ratios [OR] per standard deviation) using a stepwise procedure were apolipoprotein B/apolipoprotein A1 ratio (1.40), kallikrein (0.73), lipoprotein a (1.29), matrix metalloproteinase 9 (1.30), the interaction term IP-10/CXCL10×women (0.69), and the interaction term thrombospondin 4×men (1.38). The composite risk of these biomarkers added significantly to the traditional risk factor model with a net reclassification improvement of 14% (P=0.0002), whereas the receiver operating characteristic area increased from 0.757 to 0.791, P=0.0004. CONCLUSIONS: Novel protein biomarker models improve identification of 10-year MI risk above and beyond traditional risk factors with 14% better allocation to either high or low risk group.

Modified radial v/s biatrial maze for atrial fibrillation in rheumatic valvular heart surgery.

BACKGROUND: Atrial fibrillation (AF) is commonest sustained atrial arrhythmia producing high morbidity. Although Cox's Maze III procedure cures AF in majority, reduced atrial transport function (ATF) is a concern. Radial approach with ablation lines radial from sinus node towards atrioventricular annulii and parallel to atrial coronary arteries, has shown better ATF. METHODS: Single blind open randomized prospective study of 80 patients was undertaken in two groups (40 each) of modified Cox's maze III and modified radial approach, to evaluate conversion to normal sinus rhythm (NSR) and ATF. Patients undergoing surgery for rheumatic valvular heart disease with continuous AF were prospectively randomized. Ablation lines were created with radiofrequency (RF) bipolar coagulation with cryoablation for the isthmal lesions and coronary sinus. Results were compared at 6 months and ATF was evaluated by atrial filling fraction (AFF) and A/E ratio on echocardiography. RESULTS: The rate of conversion to NSR in both groups was statistically insignificant by Fisher's exact test (p > 0.05). ATF was better in modified radial approach compared to modified Cox's Maze III (A/E compared by unpaired t test:0.52 ± 0.08 v/s 0.36 ± 0.10; p < 0.05. AFF compared using Mann Whitney U test: median AFF for radial group was 23 v/s 20 for biatrial group; p < 0.05). DISCUSSION: In patients with AF undergoing rheumatic valvular surgery, radiofrequency radial approach is as effective as modified Cox's maze III for conversion to NSR with better atrial transport function.

Variant priorization and analysis incorporating problematic regions of the genome.

In case-control studies of rare Mendelian disorders and complex diseases, the power to detect variant and gene-level associations of a given effect size is limited by the size of the study sample. Paradoxically, low statistical power may increase the likelihood that a statistically significant finding is also a false positive. The prioritization of variants based on call quality, putative effects on protein function, the predicted degree of deleteriousness, and allele frequency is often used as a mechanism for reducing the occurrence of false positives, while preserving the set of variants most likely to contain true disease associations. We propose that specificity can be further improved by considering errors that are specific to the regions of the genome being sequenced. These problematic regions (PRs) are identified a-priori and are used to down-weight constitutive variants in a case-control analysis. Using samples drawn from 1000-Genomes, we illustrate the utility of PRs in identifying true variant and gene associations using a case-control study on a known Mendelian disease, cystic fibrosis (CF).

Microfluidic strategies applied to biomarker discovery and validation for multivariate diagnostics.

Complex diseases are caused by combinatorial genetic, environmental and lifestyle factors. The emergence of multibiomarker tests to define these diseases and to identify the early, presymptomatic stages offers several advantages to the conventional use of single marker tests. The development of multibiomarker protein-based tests remains constrained by technological and operational limitations in assaying hundreds to thousands of proteins in thousands of samples. In order to develop a multibiomarker test that stratifies risk for Type 2 diabetes, we took a candidate-driven immunoassay approach utilizing a microfluidics platform to analyze 89 candidate proteins in thousands of samples, which allowed us to move from discovery to a commercial test in 2 years. Future multibiomarker test development will be enhanced by advancements in the number of proteins that can be analyzed, analytical sensitivity and throughput, and sample volume requirements, all of which depend on the further advancement of microfluidics, detection technologies and affinity-based reagents.

Intracardiac bronchogenic cyst.

Bronchogenic cysts are congenital malformations that originate from the primitive foregut and are commonly located in the mediastinum or lung. The heart is one of the sites for atypical locations of such cysts. In this report, we describe an intracardiac bronchogenic cyst seen as an incidental finding during patch closure of a ventricular septal defect.

Cardiac calcified amorphous tumor.

Cardiac calcified amorphous tumor is a rare pseudoneoplastic intracavitary mass composed of calcium deposits in a background of amorphous degenerating fibrin. We report occurrence of this lesion in the right atrium in two male patients. These were accompanied by calcific occlusion of the inferior vena cava and right pulmonary artery.

Intraoperative ablation of atrial fibrillation - replication of the Cox's maze III procedure with re-usable radiofrequency and cryoablation devices.

The cut and sew Cox's maze III procedure is time-consuming. Therefore, various energy sources have been used for ablation, to replace the cut and sew technique. We have used the bipolar radiofrequency output of a standard electrosurgical generator with re-usable forceps for replicating the Cox's maze III procedure from August 1996. In addition, re-usable nitrous oxide based cryoprobe has been used at the atrioventricular valve annuli and on the coronary sinus. The 85.7% cure rate at one year compares with that for surgical ablation of atrial fibrillation using alternative energy sources.

Aortic pseudo-aneurysm: cause of life-threatening hemoptysis in a 13-month-old child.

Aortic aneurysms and pseudo-aneurysms are a rare occurrence in the pediatric age group. True aneurysms are usually related to infection or to inherited disorders while pseudo-aneurysms occur following trauma or infection. We present a case of a pseudo-aneurysm of the descending thoracic aorta in a 13-month-old child, who presented with life-threatening massive hemoptysis. Though no clear-cut etiologic factor was identified on clinical examination and investigations, presence of neutrophilic infiltration in the wall suggested an infective nature.

Cardiac valvular inflammatory pseudotumor.

Inflammatory pseudotumors are quasineoplastic lesions that occur in the lungs as well as other extrapulmonary sites. The heart is an uncommon site of origin. We report a valvular pseudotumor that produced chronic mitral and aortic regurgitation in an elderly woman.

Rhabdomyoma of the right atrium: report of a case.

Rhabdomyomas are the most common primary cardiac tumors in childhood, and are considered to be congenital lesions. They are uncommon in adolescents and adults due to their tendency for spontaneous regression. Majority of them are located in the ventricular chambers, and are also associated with tuberous sclerosis. The indications for surgery include hemodynamic compromise and intractable arrhythmias. We describe a right atrial rhabdomyoma in a previously healthy 16-year-old girl who presented with palpitation and dizziness of recent onset. Postoperative evaluation had not revealed stigmata of tuberous sclerosis.

Efficacy of three different ablative procedures to treat atrial fibrillation in patients with valvular heart disease: a randomised trial.

OBJECTIVES: Various modifications have been proposed to the original Cox's Maze procedure due to concerns about the long bypass and cross clamp times. The efficacy of these procedures has been studied and reported. We conducted a randomised prospective study to compare three procedures, differing in extent, of ablation in patients in atrial fibrillation who were undergoing surgery for rheumatic valvular heart disease. These procedures utilised radiofrequency in the bipolar mode. The extent of ablation was (1) biatrial (replication of the Cox Maze) (2) left atrial portion of the Cox Maze and (3) pulmonary vein isolation along with a control group (the No Maze group). Conversion rate to sinus rhythm was studied over a mid-term follow-up period. METHODS: A total of 160 patients were studied with 40 patients in each group. Antiarrhythmic drugs were not used in the three months preceding surgery and for seven days postoperatively. The patients underwent surgery for their valve disease along with the ablative procedure as per randomisation using radiofrequency microbipolar coagulation and cryoablation. They were followed up and were evaluated for symptomatic improvement, rhythm with ECG documentation and 2D echocardiography. RESULTS: Follow-up was available for 133 patients. Mid-term results showed that sinus rhythm was restored in 62.5% patients of Biatrial Maze group and 57.5% in the Left Atrial Maze. In the Pulmonary Vein Isolation Maze group, 67.5% patients converted to NSR whereas in the No Maze group only 20% patients were in sinus rhythm (p value for all the groups was 0.001 when compared to the No Maze group). The incidence of other arrhythmias was not significant and there were no other major complications. All the patients in sinus rhythm at follow-up were in NYHA functional class I-II and showed good effort tolerance. CONCLUSIONS: Results achieved with the three ablative procedures are comparable. Therefore lesser procedures viz. Left Atrial Maze and the Pulmonary Vein Isolation Maze procedures must be studied further with the additional use of antiarrhythmic drugs.

A pilot study of the association of pharmacokinetic and pharmacodynamic parameters of warfarin with the dose in patients on long-term anticoagulation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Warfarin is a widely used anticoagulant with a low therapeutic index. There is wide interindividual variation in the pharmacokinetics and pharmacodynamics of warfarin which is also reflected in the warfarin dose requirement. CYP2C9 and VKORC1 polymorphisms have been shown to affect warfarin dose requirement. However a large amount of the variation in warfarin dose remains unaccounted for. WHAT THIS STUDY ADDS: Our findings suggest that in patients who are on long-term warfarin therapy, INR : plasma 7-hydroxywarfarin concentration correlates well with warfarin requirement and also accounts for a large amount of variation in warfarin dose. AIMS: To assess the correlation between plasma total warfarin concentration, plasma 7-hydroxywarfarin concentration and INR and the weekly doses of warfarin in patients on long-term anticoagulation. METHODS: Twenty-five patients on long-term anticoagulation with warfarin were studied. Plasma total warfarin and 7-hydroxywarfarin concentrations and INR were determined. Equations were derived with the weekly warfarin dose as the dependent variable and plasma total warfarin concentration : plasma 7-hydroxywarfarin concentration, INR : plasma total warfarin concentration and INR : plasma 7-hydroxywarfarin concentration as independent variables. RESULTS: There was a good correlation between INR : plasma total warfarin concentration and the weekly dose of warfarin (y = 46.73e(-0.30x), r(2) = 0.65). There was a better correlation between INR : plasma 7-hydroxywarfarin concentration and the weekly dose of warfarin (y = 156.52x(-0.63), r(2) = 0.74) CONCLUSIONS: Pharmacokinetic parameters along with INR seem to correlate with the weekly doses of warfarin in patients on long-term anticoagulation. These parameters may therefore be useful for predicting warfarin doses.

Persistent left SVC with absent right SVC: a rare anomaly.

A persistent left superior vena cava is an anomaly found in association with many congenital heart disorders. However its presence along with absence of the right superior vena cava is a very rare congenital anomaly. This anomaly has implications in various interventional procedures and in cardiac surgery. We present here a case with absence of the right SVC and a persistent left SVC found in association with an ostium secundum atrial septal defect.

Localized pericardial constriction resulting in a "dumbbell" heart.

We describe an unusual case of a young man presenting with calcific constrictive pericarditis. The patient had a history of restrictive cardiomyopathy and pericardial effusion during infancy and received antituberculous treatment. Investigations revealed the presence of thickened pericardium and a thickened calcific constrictive band around the atrioventricular groove posteriorly and over the infundibulum anteriorly. Intraoperatively, the band caused the heart to have a "dumbbell" appearance. A pericardiectomy was performed along with excision of the constricting band. The patient had an uneventful recovery.