TL;DR: An algorithm is presented which is mathematically sound and computationally efficient to accurately analyze CNV in a DNA sample utilizing a nanofluidic device, known as the digital array, based on results from probability theory and statistics.
Abstract: Copy Number Variations (CNVs) of regions of the human genome have been associated with multiple diseases. We present an algorithm which is mathematically sound and computationally efficient to accurately analyze CNV in a DNA sample utilizing a nanofluidic device, known as the digital array. This numerical algorithm is utilized to compute copy number variation and the associated statistical confidence interval and is based on results from probability theory and statistics. We also provide formulas which can be used as close approximations.
TL;DR: Random and independent distribution of target DNA molecules throughout partitions, which is critical to accurate digital PCR measurement, was demonstrated by spatial distribution analysis and can be applied to other digital PCR studies to improve confidence in such measurements.
Abstract: Digital polymerase chain reaction (PCR) is a promising technique for estimating target DNA copy number. PCR solution is distributed throughout numerous partitions, and following amplification, target DNA copy number is estimated based on the proportion of partitions containing amplified DNA. Here, we identify approaches for obtaining reliable digital PCR data. Single molecule amplification efficiency was significantly improved following fragmentation of total DNA and bias in copy number estimates reduced by analysis of short intact target DNA fragments. Random and independent distribution of target DNA molecules throughout partitions, which is critical to accurate digital PCR measurement, was demonstrated by spatial distribution analysis. The estimated relative uncertainty for target DNA concentration was under 6% when analyzing five digital panels comprising 765 partitions each, provided the panels contained an average of 212 to 3,365 template molecules. Partition volume was a major component of this uncertainty estimate. These findings can be applied to other digital PCR studies to improve confidence in such measurements.
TL;DR: The purpose of this paper is mainly tutorial, to describe mathematically and intuitively the fundamental relationships necessary to understand digital array processing.
Abstract: With the advent of high-speed digital electronics, it has become feasible to use digital computers and special purpose digital processors to perform the computational tasks associated with signal reception using an antenna or directional array. The purpose of this paper is mainly tutorial, to describe mathematically and intuitively the fundamental relationships necessary to understand digital array processing. It is hoped that those readers with a background in antenna theory or array processing will see some of the advantages digital processing can offer, while those with a background in digital signal processing recognize the array processing area as a potential application for multi-dimensional signal processing theory.
TL;DR: The use of the digital array enables accurate measurement of gene copy numbers and is of significant value in CNV studies.
Abstract: Copy number variations (CNVs) in the human genome are conventionally detected using high-throughput scanning technologies, such as comparative genomic hybridization and high-density single nucleotide polymorphism (SNP) microarrays, or relatively low-throughput techniques, such as quantitative polymerase chain reaction (PCR). All these approaches are limited in resolution and can at best distinguish a twofold (or 50%) difference in copy number. We have developed a new technology to study copy numbers using a platform known as the digital array, a nanofluidic biochip capable of accurately quantitating genes of interest in DNA samples. We have evaluated the digital array's performance using a model system, to show that this technology is exquisitely sensitive, capable of differentiating as little as a 15% difference in gene copy number (or between 6 and 7 copies of a target gene). We have also analyzed commercial DNA samples for their CYP2D6 copy numbers and confirmed that our results were consistent with those obtained independently using conventional techniques. In a screening experiment with breast cancer and normal DNA samples, the ERBB2 gene was found to be amplified in about 35% of breast cancer samples. The use of the digital array enables accurate measurement of gene copy numbers and is of significant value in CNV studies.
TL;DR: In this article, the authors provide an overview of the state-of-the-art mmW massive antenna array designs and comparison among three architectures, namely digital array, sub-array, and fully-connected hybrid array.
Abstract: Millimeter wave (mmW) communications is the key enabler of 5G cellular networks due to vast spectrum availability that could boost peak rate and capacity. Due to increased propagation loss in mmW band, transceivers with massive antenna array are required to meet link budget, but their power consumption and cost become limiting factors for commercial systems. Radio designs based on hybrid digital and analog array architectures and the usage of radio frequency (RF) signal processing via phase shifters have emerged as potential solutions to improve energy efficiency and deliver performances close to digital arrays. In this paper, we provide an overview of the state-of-the-art mmW massive antenna array designs and comparison among three architectures, namely digital array, sub-array, and fully-connected hybrid array. The comparison of performance, power, and area for these three architectures is performed for three representative 5G use cases, which cover a range of pre-beamforming SNR and multiplexing regimes. This is the first study to comprehensively model and analyze all design aspects and criteria including: 1) optimal linear precoder, 2) impact of quantization error in DAC and phase shifters, 3) RF signal distribution network, 4) power and area estimation based on state-of-the-art mmW circuits including baseband precoding, digital signal distribution, DACs, oscillators and mixers, phase shifters, RF signal distribution, and power amplifiers. The results show that the digital array is the most power and area efficient compared against optimal design for each architecture. Our analysis shows digital array benefits greatly from multi-user multiplexing. The analysis also reveals that sub-array is limited by reduced beamforming gain due to array partitioning, and system bottleneck of the fully-connected hybrid architecture is the excessively power hungry RF signal distribution network.