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.

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.

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.

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.

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.

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.

Takayasu's arteritis with ostial and left main coronary artery stenosis.

Takayasu's arteritis with coronary artery involvement is rare, and there is little published information on the subject. Coronary angiographic and histopathologic studies have revealed coronary artery lesions in 9% to 11% of cases. Coronary artery involvement consists mostly of stenosis or occlusion of the coronary ostia. We report the case of a 19-year-old woman who presented with crescendo angina. Upon investigation, we found that our patient had ostial and left main coronary arterial stenosis with left-dominant circulation; therefore, we decided that an arterial Y graft, performed on a beating heart, would provide better perfusion to the compromised myocardium than would a single graft to the left anterior descending artery. In addition, use of the Y graft obviated the need to perform a proximal anastomosis on an inflamed, edematous ascending aorta, and it conferred long-term graft patency of the internal mammary arteries. Timely coronary artery bypass grafting relieved our patient's angina, and in early follow-up she has shown good effort tolerance.

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.

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.

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.

Reduced size of the amygdala in individuals with 47,XXY and 47,XXX karyotypes.

The excess of 47,XXX and 47,XXY karyotypes found in cytogenetic screening studies of individuals with schizophrenia has given support for an increased risk of psychiatric illness among men and women with sex chromosomal aneuploidy (SCA). Mesial temporal lobe structures, including the amygdala and hippocampus, are thought to be associated with abnormalities of mood and behavior in humans and in the neurobiology of schizophrenia. This study focuses on variations in volumes of mesial temporal lobe structures in men and women with SCA. Utilizing an unselected birth cohort of subjects with SCA and high-resolution magnetic resonance imaging (MRI), we investigated the neuroanatomical consequences of a supernumerary X chromosome on the morphology of the amygdala and hippocampus. Regional and total brain volumes were measured in 10 subjects with 47,XXY, 10 subjects with 47,XXX, and 20 euploid controls. Amygdala volumes were significantly reduced in men with 47,XXY, compared to control men, while the decrease in women with 47,XXX was not as pronounced. Hippocampus volumes were preserved in both groups, compared to same-gender controls. Longitudinal studies of SCA individuals have shown an increased incidence of mild psychopathology and behavioral dysfunction in men with 47,XXY and more overt psychiatric illness in women with 47,XXX, compared to control populations. The alteration in amygdala volumes in individuals with a supernumerary X chromosome may provide a neuroanatomic basis for these findings.

Brain development in Turner syndrome: a magnetic resonance imaging study.

Turner syndrome (TS) results from the absence of an X chromosome in females. This genetic condition is associated with specific cognitive deficits and variations in brain volumes. The goal of this study was to use high-resolution magnetic resonance imaging (MRI) to determine morphological variations in TS and to investigate the effects of parental origin of the X chromosome on brain development in TS. MRI brain scans were acquired from 26 girls with TS and 26 age- and gender-matched controls. Seventeen of the TS subjects had a maternally inherited X chromosome (Xm), and nine of the subjects had a paternally inherited X chromosome (Xp). Rater-blind morphometric analyses were conducted to compare tissue volume differences between girls with TS and controls. Three-way analyses were used to compare subgroups and controls. Subjects with TS demonstrated bilateral decreases in parietal gray and occipital white matter accompanied by increased cerebellar gray matter. Subjects with Xm showed decreased occipital white matter and increased cerebellar gray matter compared to controls. No differences were found in comparisons between subjects with Xp and controls or between subjects with Xm and Xp. Results suggest that X monosomy affects posterior cerebral and cerebellar anatomy in TS. While differences between comparisons of Xm and Xp to controls might suggest an imprinting effect, no significant differences were found when the two subgroups were directly compared to each other. Further investigation into the possible role of genomic imprinting is therefore warranted.

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.

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.