Abstract:
The present disclosure discusses a system and method for disease module detection. More particularly, a protein network and list of seed proteins are provided to the system. The system iteratively selects one or more candidate proteins for inclusion in the list of seed proteins. The system calculates a connectivity factor for each of the connections of the candidate proteins to proteins listed as seed proteins. Responsive to the calculated connectivity factors the system adds one or more of the candidate proteins to list of seed proteins. At the end of the iterative process the list of seed proteins can be indicative of the disease module.

Description:
RELATED APPLICATION 
       [0001]    This application claims priority to U.S. Provisional Patent Application No. 61/881,042, titled “DIAMOND-Disease Module Detection algorithm”, filed Sep. 23, 2013, which is incorporated herein by reference in its entirety for all purposes. 
     
    
     GOVERNMENT SUPPORT 
       [0002]    This invention was made with government support under P50-HG004233 and 1U01HL108630-01 by the National Institutes of Health (NIH), 11645021 and W911NF-12-C-0028 by DARPA, W911NF-09-02-0053 by The US Army Research Laboratory, N000141010968 by The Office of Naval Research, and WMDBRBAA07-J-2-0035 and BRBAA08-Per4-C-2-0033 by the Defense Threat Reduction Agency. The government has certain rights in the invention. 
     
    
     FIELD OF THE DISCLOSURE 
       [0003]    This disclosure generally relates to systems and methods for determining networks of genes associated with a disease phenotype. In particular, this disclosure relates to systems and methods for establishing a disease module responsive to a set of seed genes. 
       BACKGROUND OF THE DISCLOSURE 
       [0004]    Proteins interact within the human interactome to form protein topologies. The patho-biological properties of a disease and its clinical manifestations can be linked to the clusters that the proteins form. To date, the locations of few disease clusters have been located within the interactome, and those disease clusters that have been located are often incomplete. 
       BRIEF SUMMARY OF THE DISCLOSURE 
       [0005]    According to one aspect of the disclosure, a method for determining a disease cluster includes receiving, by a connectivity module, an indication of a protein network. The protein network can include a plurality of interconnected proteins. The method can also include receiving, by the connectivity module, an indication of a plurality of seed proteins within the protein network that are associated with the disease. Until a criterion is met, the method can iteratively include selecting, by the connectivity module, one or more candidate proteins and calculating a connectivity factor for each of the one or more candidate proteins. The method can further include updating the plurality of seed proteins to include one of the one or more candidate proteins based on the calculated connectivity factor. The method may also include providing, responsive to the satisfactory of the criterion, an indication of a portion of the plurality of interconnected proteins associated with the disease based on the updated list of seed proteins. 
         [0006]    In some implementations, the method can also include ranking the connectivity factor for each of the one or more candidate proteins. The method can also include updating the plurality of seed proteins to include a candidate protein from the one or more candidate proteins with the lowest connectivity factor. 
         [0007]    In certain implementations, the one or more candidate proteins are connected to at least one of the plurality of seed proteins in the protein network. The one or more candidate proteins can also be connected to the at least one of the plurality of seed proteins through an intermediate protein. 
         [0008]    In some implementations, the criterion is a predetermined number of iterations. The method may also include calculating a probability for each connection of the one or more candidate proteins that each connection is connected to one of the plurality of seed proteins. 
         [0009]    The method can also include summing, for each of the one or more candidate proteins, the probabilities that each connection of the one or more candidate proteins is connected to one of the plurality of seed proteins. In some implementations, the protein network is a human interactome. The method can further include updating the plurality of seed proteins to include two or more of the one or more candidate proteins. 
         [0010]    According to another aspect of the disclosure, a system for determining a disease cluster can include a storage device configured to store an indication of a protein network and an indication of a plurality of seed proteins. The protein network can include a plurality of interconnected proteins. The plurality of seed proteins can be one or more proteins within the protein network that are associated with a disease. The system can also include a connectivity module. The connectivity module can be configured to retrieve the indication of the protein network and the indication of the plurality of seed proteins from the storage device. The connectivity module can further be configured to select one or more candidate proteins. The connectivity module can also calculate a connectivity factor for each of the one or more candidate proteins. The connectivity module may also update the plurality of seed proteins to include one of the one or more candidate proteins based on the calculated connectivity factor for each of the one or more candidate proteins. The connectivity module can also provide an indication of a portion of the plurality of interconnected proteins associated with the disease. 
         [0011]    In some implementations, the connectivity module is also configured to rank the connectivity factor for each of the one or more candidate proteins. The connectivity module can also be configured to update the plurality of seed proteins to include a candidate protein from the one or more candidate proteins with the lowest connectivity factor. 
         [0012]    In some implementations, one or more candidate proteins can be connected to at least one of the plurality of seed proteins in the protein network. The one or more candidate proteins can be connected to the at least one of the plurality of seed proteins through an intermediate protein. 
         [0013]    In some implementations, the criterion is a predetermined number of iterations. The connectivity module can be configured to calculate a probability for each connection of the one or more candidate proteins that each connection is connected to one of the plurality of seed proteins. The connectivity module can also be configured to sum, for each of the one or more candidate proteins, the probabilities that each connection of the one or more candidate proteins is connected to one of the plurality of seed proteins. In some implementations, the connectivity module can be configured to update the plurality of seed proteins to include two or more of the one or more candidate proteins. In some implementations, the protein network is a human interactome. 
         [0014]    The details of various embodiments of the disclosure are set forth in the accompanying drawings and the description below. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0015]    The foregoing and other objects, aspects, features, and advantages of the disclosure will become more apparent and better understood by referring to the following description taken in conjunction with the accompanying drawings, in which: 
           [0016]      FIG. 1A  is a block diagram illustrating an example network environment including client machines in communication with remote machines. 
           [0017]      FIGS. 1B and 1C  are block diagrams illustrating example computing devices useful in connection with the methods and systems described herein. 
           [0018]      FIG. 2  illustrates an example protein clustering system. 
           [0019]      FIG. 3  illustrates an example method for generating a disease cluster using the example protein clustering system illustrated in  FIG. 2 . 
           [0020]      FIGS. 4-7  illustrate an example protein network at different steps in the method illustrated in  FIG. 3 . 
       
    
    
       [0021]    The features and advantages of the present invention will become more apparent from the detailed description set forth below when taken in conjunction with the drawings, in which like reference characters identify corresponding elements throughout. In the drawings, like reference numbers generally indicate identical, functionally similar, and/or structurally similar elements. 
       DETAILED DESCRIPTION 
       [0022]    For purposes of reading the description of the various embodiments below, the following descriptions of the sections of the specification and their respective contents may be helpful: 
         [0023]    Section A describes a network environment and computing environment which may be useful for practicing embodiments described herein; and 
         [0024]    Section B describes embodiments of systems and methods for detecting disease modules. 
       A. Computing and Network Environment 
       [0025]    Prior to discussing specific embodiments of the present solution, it may be helpful to describe aspects of the operating environment as well as associated system components (e.g., hardware elements) in connection with the methods and systems described herein. Referring to  FIG. 1A , an embodiment of a network environment is depicted. In brief overview, the network environment includes one or more clients  101   a - 101   n  (also generally referred to as local machine(s)  101 , client(s)  101 , client node(s)  101 , client machine(s)  101 , client computer(s)  101 , client device(s)  101 , endpoint(s)  101 , or endpoint node(s)  101 ) in communication with one or more servers  106   a - 106   n  (also generally referred to as server(s)  106 , node  106 , or remote machine(s)  106 ) via one or more networks  104 . In some embodiments, a client  101  has the capacity to function as both a client node seeking access to resources provided by a server and as a server providing access to hosted resources for other clients  101   a - 101   n.    
         [0026]    Although  FIG. 1A  shows a network  104  between the clients  101  and the servers  106 , the clients  101  and the servers  106  may be on the same network  104 . The network  104  can be a local-area network (LAN), such as a company Intranet, a metropolitan area network (MAN), or a wide area network (WAN), such as the Internet or the World Wide Web. In some embodiments, there are multiple networks  104  between the clients  101  and the servers  106 . In one of these embodiments, a network  104 ′ (not shown) may be a private network and a network  104  may be a public network. In another of these embodiments, a network  104  may be a private network and a network  104 ′ a public network. In still another of these embodiments, networks  104  and  104 ′ may both be private networks. 
         [0027]    The network  104  may be any type and/or form of network and may include any of the following: a point-to-point network, a broadcast network, a wide area network, a local area network, a telecommunications network, a data communication network, a computer network, an ATM (Asynchronous Transfer Mode) network, a SONET (Synchronous Optical Network) network, a SDH (Synchronous Digital Hierarchy) network, a wireless network and a wireline network. In some embodiments, the network  104  may comprise a wireless link, such as an infrared channel or satellite band. The topology of the network  104  may be a bus, star, or ring network topology. The network  104  may be of any such network topology as known to those ordinarily skilled in the art capable of supporting the operations described herein. The network may comprise mobile telephone networks utilizing any protocol(s) or standard(s) used to communicate among mobile devices, including AMPS, TDMA, CDMA, GSM, GPRS, UMTS, WiMAX, 3G or 4G. In some embodiments, different types of data may be transmitted via different protocols. In other embodiments, the same types of data may be transmitted via different protocols. 
         [0028]    In some embodiments, the system may include multiple, logically-grouped servers  106 . In one of these embodiments, the logical group of servers may be referred to as a server farm  38  or a machine farm  38 . In another of these embodiments, the servers  106  may be geographically dispersed. In other embodiments, a machine farm  38  may be administered as a single entity. In still other embodiments, the machine farm  38  includes a plurality of machine farms  38 . The servers  106  within each machine farm  38  can be heterogeneous—one or more of the servers  106  or machines  106  can operate according to one type of operating system platform (e.g., WINDOWS, manufactured by Microsoft Corp. of Redmond, Wash.), while one or more of the other servers  106  can operate on according to another type of operating system platform (e.g., Unix or Linux). 
         [0029]    In one embodiment, servers  106  in the machine farm  38  may be stored in high-density rack systems, along with associated storage systems, and located in an enterprise data center. In this embodiment, consolidating the servers  106  in this way may improve system manageability, data security, the physical security of the system, and system performance by locating servers  106  and high performance storage systems on localized high performance networks. Centralizing the servers  106  and storage systems and coupling them with advanced system management tools allows more efficient use of server resources. 
         [0030]    The servers  106  of each machine farm  38  do not need to be physically proximate to another server  106  in the same machine farm  38 . Thus, the group of servers  106  logically grouped as a machine farm  38  may be interconnected using a wide-area network (WAN) connection or a metropolitan-area network (MAN) connection. For example, a machine farm  38  may include servers  106  physically located in different continents or different regions of a continent, country, state, city, campus, or room. Data transmission speeds between servers  106  in the machine farm  38  can be increased if the servers  106  are connected using a local-area network (LAN) connection or some form of direct connection. Additionally, a heterogeneous machine farm  38  may include one or more servers  106  operating according to a type of operating system, while one or more other servers  106  execute one or more types of hypervisors rather than operating systems. In these embodiments, hypervisors may be used to emulate virtual hardware, partition physical hardware, virtualize physical hardware, and execute virtual machines that provide access to computing environments. Hypervisors may include those manufactured by VMWare, Inc., of Palo Alto, Calif.; the Xen hypervisor, an open source product whose development is overseen by Citrix Systems, Inc.; the Virtual Server or virtual PC hypervisors provided by Microsoft or others. 
         [0031]    In order to manage a machine farm  38 , at least one aspect of the performance of servers  106  in the machine farm  38  should be monitored. Typically, the load placed on each server  106  or the status of sessions running on each server  106  is monitored. In some embodiments, a centralized service may provide management for machine farm  38 . The centralized service may gather and store information about a plurality of servers  106 , respond to requests for access to resources hosted by servers  106 , and enable the establishment of connections between client machines  101  and servers  106 . 
         [0032]    Management of the machine farm  38  may be de-centralized. For example, one or more servers  106  may comprise components, subsystems and modules to support one or more management services for the machine farm  38 . In one of these embodiments, one or more servers  106  provide functionality for management of dynamic data, including techniques for handling failover, data replication, and increasing the robustness of the machine farm  38 . Each server  106  may communicate with a persistent store and, in some embodiments, with a dynamic store. 
         [0033]    Server  106  may be a file server, application server, web server, proxy server, appliance, network appliance, gateway, gateway, gateway server, virtualization server, deployment server, SSL VPN server, or firewall. In one embodiment, the server  106  may be referred to as a remote machine or a node. In another embodiment, a plurality of nodes  290  may be in the path between any two communicating servers. 
         [0034]    In one embodiment, the server  106  provides the functionality of a web server. In another embodiment, the server  106 a receives requests from the client  101 , forwards the requests to a second server  106 b and responds to the request by the client  101  with a response to the request from the server  106 b. In still another embodiment, the server  106  acquires an enumeration of applications available to the client  101  and address information associated with a server  106 ′ hosting an application identified by the enumeration of applications. In yet another embodiment, the server  106  presents the response to the request to the client  101  using a web interface. In one embodiment, the client  101  communicates directly with the server  106  to access the identified application. In another embodiment, the client  101  receives output data, such as display data, generated by an execution of the identified application on the server  106 . 
         [0035]    The client  101  and server  106  may be deployed as and/or executed on any type and form of computing device, such as a computer, network device or appliance capable of communicating on any type and form of network and performing the operations described herein.  FIGS. 1B and 1C  depict block diagrams of a computing device  100  useful for practicing an embodiment of the client  101  or a server  106 . As shown in  FIGS. 1B and 1C , each computing device  100  includes a central processing unit  121 , and a main memory unit  122 . As shown in  FIG. 1B , a computing device  100  may include a storage device  128 , an installation device  116 , a network interface  118 , an I/O controller  123 , display devices  124   a - 101   n,  a keyboard  126  and a pointing device  127 , such as a mouse. The storage device  128  may include, without limitation, an operating system and/or software. As shown in  FIG. 1C , each computing device  100  may also include additional optional elements, such as a memory port  103 , a bridge  170 , one or more input/output devices  130   a - 130   n  (generally referred to using reference numeral  130 ), and a cache memory  140  in communication with the central processing unit  121 . 
         [0036]    The central processing unit  121  is any logic circuitry that responds to and processes instructions fetched from the main memory unit  122 . In many embodiments, the central processing unit  121  is provided by a microprocessor unit, such as: those manufactured by Intel Corporation of Mountain View, Calif.; those manufactured by Motorola Corporation of Schaumburg, Ill.; those manufactured by International Business Machines of White Plains, N.Y.; or those manufactured by Advanced Micro Devices of Sunnyvale, Calif. The computing device  100  may be based on any of these processors, or any other processor capable of operating as described herein. 
         [0037]    Main memory unit  122  may be one or more memory chips capable of storing data and allowing any storage location to be directly accessed by the microprocessor  121 , such as Static random access memory (SRAM), Burst SRAM or SynchBurst SRAM (BSRAM), Dynamic random access memory (DRAM), Fast Page Mode DRAM (FPM DRAM), Enhanced DRAM (EDRAM), Extended Data Output RAM (EDO RAM), Extended Data Output DRAM (EDO DRAM), Burst Extended Data Output DRAM (BEDO DRAM), Enhanced DRAM (EDRAM), synchronous DRAM (SDRAM), JEDEC SRAM, PC100 SDRAM, Double Data Rate SDRAM (DDR SDRAM), Enhanced SDRAM (ESDRAM), SyncLink DRAM (SLDRAM), Direct Rambus DRAM (DRDRAM), Ferroelectric RAM (FRAM), NAND Flash, NOR Flash and Solid State Drives (SSD). The main memory  122  may be based on any of the above described memory chips, or any other available memory chips capable of operating as described herein. In the embodiment shown in  FIG. 1B , the processor  121  communicates with main memory  122  via a system bus  150  (described in more detail below).  FIG. 1C  depicts an embodiment of a computing device  100  in which the processor communicates directly with main memory  122  via a memory port  103 . For example, in  FIG. 1C  the main memory  122  may be DRDRAM. 
         [0038]      FIG. 1C  depicts an embodiment in which the main processor  121  communicates directly with cache memory  140  via a secondary bus, sometimes referred to as a backside bus. In other embodiments, the main processor  121  communicates with cache memory  140  using the system bus  150 . Cache memory  140  typically has a faster response time than main memory  122  and is typically provided by SRAM, BSRAM, or EDRAM. In the embodiment shown in  FIG. 1C , the processor  121  communicates with various I/O devices  130  via a local system bus  150 . Various buses may be used to connect the central processing unit  121  to any of the I/O devices  130 , including a VESA VL bus, an ISA bus, an EISA bus, a MicroChannel Architecture (MCA) bus, a PCI bus, a PCI-X bus, a PCI-Express bus, or a NuBus. For embodiments in which the I/O device is a video display  124 , the processor  121  may use an Advanced Graphics Port (AGP) to communicate with the display  124 .  FIG. 1C  depicts an embodiment of a computer  100  in which the main processor  121  may communicate directly with I/O device  130 b, for example via HYPERTRANSPORT, RAPIDIO, or INFINIBAND communications technology.  FIG. 1C  also depicts an embodiment in which local busses and direct communication are mixed: the processor  121  communicates with I/O device  130   a  using a local interconnect bus while communicating with I/O device  130   b  directly. 
         [0039]    A wide variety of I/O devices  130   a - 130   n  may be present in the computing device  100 . Input devices include keyboards, mice, trackpads, trackballs, microphones, dials, touch pads, and drawing tablets. Output devices include video displays, speakers, inkjet printers, laser printers, projectors and dye-sublimation printers. The I/O devices may be controlled by an I/O controller  123  as shown in  FIG. 1B . The I/O controller may control one or more I/O devices such as a keyboard  126  and a pointing device  127 , e.g., a mouse or optical pen. Furthermore, an I/O device may also provide storage and/or an installation medium  116  for the computing device  100 . In still other embodiments, the computing device  100  may provide USB connections (not shown) to receive handheld USB storage devices such as the USB Flash Drive line of devices manufactured by Twintech Industry, Inc. of Los Alamitos, Calif. 
         [0040]    Referring again to  FIG. 1B , the computing device  100  may support any suitable installation device  116 , such as a disk drive, a CD-ROM drive, a CD-R/RW drive, a DVD-ROM drive, a flash memory drive, tape drives of various formats, USB device, hard-drive or any other device suitable for installing software and programs. The computing device  100  can further include a storage device, such as one or more hard disk drives or redundant arrays of independent disks, for storing an operating system and other related software, and for storing application software programs such as any program or software  120  for implementing (e.g., configured and/or designed for) the systems and methods described herein. Optionally, any of the installation devices  116  could also be used as the storage device. Additionally, the operating system and the software can be run from a bootable medium, for example, a bootable CD. 
         [0041]    Furthermore, the computing device  100  may include a network interface  118  to interface to the network  104  through a variety of connections including, but not limited to, standard telephone lines, LAN or WAN links (e.g., 802.11, T1, T3, 56 kb, X.25, SNA, DECNET), broadband connections (e.g., ISDN, Frame Relay, ATM, Gigabit Ethernet, Ethernet-over-SONET), wireless connections, or some combination of any or all of the above. Connections can be established using a variety of communication protocols (e.g., TCP/IP, IPX, SPX, NetBIOS, Ethernet, ARCNET, SONET, SDH, Fiber Distributed Data Interface (FDDI), RS232, IEEE 802.11, IEEE 802.11a, IEEE 802.11b, IEEE 802.11g, IEEE 802.11n, CDMA, GSM, WiMax and direct asynchronous connections). In one embodiment, the computing device  100  communicates with other computing devices  100 ′ via any type and/or form of gateway or tunneling protocol such as Secure Socket Layer (SSL) or Transport Layer Security (TLS), or the Citrix Gateway Protocol manufactured by Citrix Systems, Inc. of Ft. Lauderdale, Fla. The network interface  118  may comprise a built-in network adapter, network interface card, PCMCIA network card, card bus network adapter, wireless network adapter, USB network adapter, modem or any other device suitable for interfacing the computing device  100  to any type of network capable of communication and performing the operations described herein. 
         [0042]    In some embodiments, the computing device  100  may comprise or be connected to multiple display devices  124   a - 124   n,  which each may be of the same or different type and/or form. As such, any of the I/O devices  130   a - 130   n  and/or the I/O controller  123  may comprise any type and/or form of suitable hardware, software, or combination of hardware and software to support, enable or provide for the connection and use of multiple display devices  124   a - 124   n  by the computing device  100 . For example, the computing device  100  may include any type and/or form of video adapter, video card, driver, and/or library to interface, communicate, connect or otherwise use the display devices  124   a - 124   n.  In one embodiment, a video adapter may comprise multiple connectors to interface to multiple display devices  124   a - 124   n.  In other embodiments, the computing device  100  may include multiple video adapters, with each video adapter connected to one or more of the display devices  124   a - 124   n.  In some embodiments, any portion of the operating system of the computing device  100  may be configured for using multiple displays  124   a - 124   n.  In other embodiments, one or more of the display devices  124   a - 124   n  may be provided by one or more other computing devices, such as computing devices  100   a  and  100   b  connected to the computing device  100 , for example, via a network. These embodiments may include any type of software designed and constructed to use another computer&#39;s display device as a second display device  124   a  for the computing device  100 . One ordinarily skilled in the art will recognize and appreciate the various ways and embodiments that a computing device  100  may be configured to have multiple display devices  124   a - 124   n.    
         [0043]    In further embodiments, an I/O device  130  may be a bridge between the system bus  150  and an external communication bus, such as a USB bus, an Apple Desktop Bus, an RS-232 serial connection, a SCSI bus, a FireWire bus, a FireWire 800 bus, an Ethernet bus, an AppleTalk bus, a Gigabit Ethernet bus, an Asynchronous Transfer Mode bus, a FibreChannel bus, a Serial Attached small computer system interface bus, or a HDMI bus. 
         [0044]    A computing device  100  of the sort depicted in  FIGS. 1B and 1C  typically operates under the control of operating systems, which control scheduling of tasks and access to system resources. The computing device  100  can be running any operating system such as any of the versions of the MICROSOFT WINDOWS operating systems, the different releases of the Unix and Linux operating systems, any version of the MAC OS for Macintosh computers, any embedded operating system, any real-time operating system, any open source operating system, any proprietary operating system, any operating systems for mobile computing devices, or any other operating system capable of running on the computing device and performing the operations described herein. Typical operating systems include, but are not limited to: Android, manufactured by Google Inc; WINDOWS 7 and 8, manufactured by Microsoft Corporation of Redmond, Wash.; MAC OS, manufactured by Apple Computer of Cupertino, Calif.; WebOS, manufactured by Research In Motion (RIM); OS/2, manufactured by International Business Machines of Armonk, N.Y.; and Linux, a freely-available operating system distributed by Caldera Corp. of Salt Lake City, Utah, or any type and/or form of a Unix operating system, among others. 
         [0045]    The computer system  100  can be any workstation, telephone, desktop computer, laptop or notebook computer, server, handheld computer, mobile telephone or other portable telecommunications device, media playing device, a gaming system, mobile computing device, or any other type and/or form of computing, telecommunications or media device that is capable of communication. The computer system  100  has sufficient processor power and memory capacity to perform the operations described herein. For example, the computer system  100  may comprise a device of the IPAD or IPOD family of devices manufactured by Apple Computer of Cupertino, Calif., a device of the PLAYSTATION family of devices manufactured by the Sony Corporation of Tokyo, Japan, a device of the NINTENDO/Wii family of devices manufactured by Nintendo Co., Ltd., of Kyoto, Japan, or an XBOX device manufactured by the Microsoft Corporation of Redmond, Wash. 
         [0046]    In some embodiments, the computing device  100  may have different processors, operating systems, and input devices consistent with the device. For example, in one embodiment, the computing device  100  is a smart phone, mobile device, tablet or personal digital assistant. In still other embodiments, the computing device  100  is an Android-based mobile device, an iPhone smart phone manufactured by Apple Computer of Cupertino, Calif., or a Blackberry handheld or smart phone, such as the devices manufactured by Research In Motion Limited. Moreover, the computing device  100  can be any workstation, desktop computer, laptop or notebook computer, server, handheld computer, mobile telephone, any other computer, or other form of computing or telecommunications device that is capable of communication and that has sufficient processor power and memory capacity to perform the operations described herein. 
         [0047]    In some embodiments, the computing device  100  is a digital audio player. In one of these embodiments, the computing device  100  is a tablet such as the Apple IPAD, or a digital audio player such as the Apple IPOD lines of devices, manufactured by Apple Computer of Cupertino, Calif. In another of these embodiments, the digital audio player may function as both a portable media player and as a mass storage device. In other embodiments, the computing device  100  is a digital audio player such as an MP3 players. In yet other embodiments, the computing device  100  is a portable media player or digital audio player supporting file formats including, but not limited to, MP3, WAV, M4A/AAC, WMA Protected AAC, AIFF, Audible audiobook, Apple Lossless audio file formats and .mov, .m4v, and .mp4 MPEG-4 (H.264/MPEG-4 AVC) video file formats. 
         [0048]    In some embodiments, the communications device  101  includes a combination of devices, such as a mobile phone combined with a digital audio player or portable media player. In one of these embodiments, the communications device  101  is a smartphone, for example, an iPhone manufactured by Apple Computer, or a Blackberry device, manufactured by Research In Motion Limited. In yet another embodiment, the communications device  101  is a laptop or desktop computer equipped with a web browser and a microphone and speaker system, such as a telephony headset. In these embodiments, the communications devices  101  are web-enabled and can receive and initiate phone calls. 
         [0049]    In some embodiments, the status of one or more machines  101 ,  106  in the network  104  is monitored, generally as part of network management. In one of these embodiments, the status of a machine may include an identification of load information (e.g., the number of processes on the machine, CPU and memory utilization), of port information (e.g., the number of available communication ports and the port addresses), or of session status (e.g., the duration and type of processes, and whether a process is active or idle). In another of these embodiments, this information may be identified by a plurality of metrics, and the plurality of metrics can be applied at least in part towards decisions in load distribution, network traffic management, and network failure recovery as well as any aspects of operations of the present solution described herein. Aspects of the operating environments and components described above will become apparent in the context of the systems and methods disclosed herein. 
       B. Detecting Disease Modules 
       [0050]    The system and methods described herein relate to determining which proteins within a protein network (also referred to as a protein topology or interactome) are associated with a predetermined disease. The system, based on the topology of a protein network and a provided set of proteins known to be associated with the disease (also referred to as seed proteins), can determine which additional proteins within the network are also associated with the disease. The proteins associated with the disease may be referred to as the disease cluster or the disease module. The proteins that are labeled as associated with the disease include the local neighborhood within the protein network that is most likely responsible for the disease phenotype. In some implementations, the creation of the disease module is based on the structure (or connections) within the protein network and requires no other inputs but the seed protein list. Accordingly, the system can be parameter-free. In some implementations, the generated disease modules can be used to identify drug targets, disease pathways and molecular mechanisms, and construct individualized disease modules for personal medicine. The system may be used to determine disease clusters in diseases such, but not limited to, asthma, Ankylosing spondylitis, Celiac Disease, Crohn Disease, Diabetes Mellitus, Graves&#39; Disease, Hashimoto Disease, Lupus, Multiple Sclerosis, Psoriasis, Rheumatoid Arthritis, and Ulcerative Colitis. 
         [0051]      FIG. 2  illustrates an example protein clustering system (PCS)  200 . In some implementations, the PCS  200  is a computing device  100 , such as the computing device  100  described above in relation to  FIGS. 1A-1C . In other implementations, the PCS  200  can be implemented by special purpose logic circuitry, such as an FPGA (field programmable gate array) or an ASIC (application specific integrated circuit). The PCS  200  can include a storage device  128  for the storage a protein network array  202 , a seed protein array  204 , and a disease cluster array  206 . The PCS  200  can also include a connectivity module  208  and a disease cluster updater  210 . 
         [0052]    The PCS  200  stores a protein network array  202  within the storage device  128 . The protein network array  202  can store data representative of a file, array, or other data source that may be read by the connectivity module  208 . The data stored within the protein network array  202  can be data representative of a protein network to be analyzed, which may be referred to as an interactome. In some implementations, the data stored within the protein network array  202  can be referred to as an indication of the protein network or simply the protein network. The protein network can capture the functional interactions between the proteins of the network in a topographical protein map. The protein network may represent the protein (or molecular) interactions that occur within cell. The connections represented within the protein network can represent the physical interactions that may occur between the molecules of the proteins that make up the protein network. A protein network is illustrated and discussed in greater detail in relation to  FIG. 4 , but in general the protein network can indicate to which proteins each of the proteins within the interactome interact. 
         [0053]    In some implementations, the data stored within the protein network array  202  (e.g., the specific protein network to be analyzed by the PCS  200 ), can be retrieved from a remote server. The protein network may include the Human Interactome, which may be compiled from the regulatory, protein-protein, metabolic, protein complex-based and kinase-substrate interactions that define a human cell&#39;s molecular interaction network. In some implementations, the protein network can be curated from scientific literature or downloaded from resources such as, but not limited to, the Human Interactome Project, IntAct, bioGRID, and STRING. 
         [0054]    A seed protein array  204  can also be stored within the PCS  200 . The seed protein array  204  can store data that indicates which proteins within the protein network that is stored within the protein network array  202  are related to a predetermined disease. For example, the seed protein array  204  may include a list of proteins that are known to be involved causing the predetermined disease. In some implementations, the seed proteins indicated by the seed protein array  204  may be an incomplete list of the proteins within the protein network that are actually associated with the predetermined disease. For example, the list of seed proteins within the seed protein array  204  may include one or more seed proteins truly actually associated with the predetermined disease and may include one or more proteins that are not actually associated with the predetermined disease. In some implementations, the seed protein array  204  is updated during each iteration of the herein described method. 
         [0055]    A disease cluster array  206  can also be stored within the PCS  200 . The disease cluster array  206  can store a list of proteins that are determined by the PCS  200  to be associated with the predetermined disease. For example, the disease cluster array  206  can be an array the length of the protein network array  202 , where every bit in the array corresponds to one of the proteins within the protein network array  202 . The bits within the disease cluster array  206  can be flagged when the PCS  200  determines that the specific protein is associated with the predetermined disease. In some implementations, each of the seed proteins stored within the seed protein array  204  are initially also indicated as associated with the predetermined disease cluster by also being stored in the disease cluster array  206 . In some implementations, the final output of the method described herein can be distorted in the disease cluster array  206 . 
         [0056]    The PCS  200  also includes a connectivity module  208  and a disease cluster updater  210 . The connectivity module  208  and the disease cluster updater  210  are discussed in greater detail in relation to  FIG. 3 . Briefly, the connectivity module  208  can calculate a connectivity factor for each of the proteins within the protein network array  202  that are connected to one of the proteins that are indicated as a seed protein by the seed protein array  204 . In some implementations, the connectivity factor indicates the probability that a selected protein in the protein network is connected to one of the seed proteins not by chance. Once the connectivity module  208  has calculated the connectivity factor for each of the proteins in the protein network, the disease cluster updater  210  ranks each of the connectivity factors and determines if any of the proteins should be added to the list of seed proteins (or the disease cluster array) for the next iteration of the calculation made by the connectivity module  208 . In some implementations, the connectivity module  208  and the disease cluster updater  210  may include applications, programs, libraries, services, tasks or any type and form of executable instructions that are by one or more processors of the PCS  200 . 
         [0057]      FIG. 3  illustrates an example method  300  for determining a disease cluster. The method  300  includes retrieving a disease protein network (step  302 ) and receiving list of seed proteins (step  304 ). A plurality of candidate proteins are selected (step  306 ). A connectivity factor for each of the plurality of candidate proteins is calculated (step  308 ). The calculated connectivity factors are ranked (step  310 ). Responsive to the ranking of the connectivity factors, the list of seed proteins is updated (step  310 ). A determination is made whether a criterion is met (step  314 ). Steps  314  to  312  are repeated until the criterion is met. Responsive to the criterion being met, an indication of the proteins associated with the disease is provided (step  316 ). 
         [0058]    As set forth above, and also referring to  FIG. 4 , a protein network is provided (step  302 ). The protein network can be provided as a data file to the PCS  200  or can be manually input into the PCS  200 .  FIG. 4  illustrates an example protein network  400 . The protein network  400  includes a plurality of proteins  402  (also referred to as nodes  402 ). The proteins  402  of the protein network  400  are interconnected to form a protein topology. Some of the proteins  402  of the protein network  400  can be classified as seed proteins  404  or as candidate proteins. In some implementations, the PCS  200  receives the protein network  400  as a data file, which may be referred to as an indication of the protein network. The data file may indicate the number of proteins  402  within the network  400 , which proteins  402  are connected, and the relative strength (or weight) of the connections. The data file may be received as a flat file, a text file, a binary file, an XML file, or a propriety file format. In some implementations, when received by the PCS  200 , the PCS  200  may load all or a portion of the protein network  400  into the connectivity module  208 . For example, the PCS  200  may load only the proteins within a predetermined distance of the seed proteins rather than loading the entire protein network. 
         [0059]    A list of seed proteins is also received (step  302 ). The received seed protein list can be loaded into the seed protein array  204 . Similar, to the received protein network  400 , the list of seed proteins can be received as a data file, which may be referred to as an indication of the seed proteins. The data file may be received as a flat file, a text file, a binary file, an XML file, or a propriety file format. Referring again to  FIG. 4 , the network  400  includes a plurality of seed proteins  404 . 
         [0060]    One or more candidate proteins can be selected within the protein network (step  306 ). In some implementations, the candidate proteins can be the proteins that are coupled with one or more of the seed proteins. Referring again to  FIG. 4 , the candidate proteins  406  are the proteins coupled with one or more of the seed proteins  404 . In some implementations, the candidate proteins  406  can be coupled with one or more of the seed proteins by one or two hops. For example, a one-hop candidate protein can be coupled to a seed protein through another protein, which can be referred to as an intermediate protein. 
         [0061]    A connectivity factor for each of the candidate proteins can be calculated (step  308 ). In some implementations, the connectivity factor for each of the candidate proteins indicates the probability or significance that the given candidate protein would be connected to a given seed protein by chance. For some diseases, seed proteins (i.e., proteins associated with a disease) form relatively larger clusters within the protein network than would be expected by chance. Different proteins within a protein network may include a different number of connections to other proteins within the network. For example, in an asthmatic patient IL 8  forms 14 connections, of which 4 are known to couple with seed proteins. However, BRCA 1  makes 239 connections, only 3 of which are to seed proteins. In some implementations, for a protein with a large number of connections, each connection with a seed protein may not be a strong an indication that the protein belongs to the disease cluster. However, for a protein with a relatively small number of total connections each connection to a seed protein can be a strong indication that the protein belongs in the disease cluster. In some implementations, the connectivity factor can be a significance of the number of connections to the seed proteins is calculated to correct for the bias that can occur when the number of connections that each protein makes varies between proteins. In some implementations, the probability that a protein with k connections would be connected to one of the k s  connections made by the seed proteins by chance is given by the hypergeometric distribution: 
         [0000]    
       
         
           
             
               
                 
                   
                     P 
                      
                     
                       ( 
                       
                         X 
                         = 
                         
                           k 
                           s 
                         
                       
                       ) 
                     
                   
                   = 
                   
                     
                       
                         
                           ( 
                           
                             
                               
                                 s 
                               
                             
                             
                               
                                 
                                   k 
                                   s 
                                 
                               
                             
                           
                           ) 
                         
                          
                         
                           ( 
                           
                             
                               
                                 
                                   N 
                                   - 
                                   s 
                                 
                               
                             
                             
                               
                                 
                                   k 
                                   - 
                                   
                                     k 
                                     s 
                                   
                                 
                               
                             
                           
                           ) 
                         
                       
                       
                         ( 
                         
                           
                             
                               N 
                             
                           
                           
                             
                               k 
                             
                           
                         
                         ) 
                       
                     
                     . 
                   
                 
               
               
                 
                   ( 
                   1 
                   ) 
                 
               
             
           
         
       
     
         [0062]    In equation 1, N denotes the total number of connections in the protein network and s denotes the number of seed proteins in the protein network. The significance of a given number of connections to the seed proteins k s  can be measured by the p-value: 
         [0000]    
       
         
           
             
               
                 
                   
                     p 
                      
                     
                       - 
                     
                      
                     value 
                   
                   = 
                   
                     
                       ∑ 
                       
                         n 
                         = 
                         
                           k 
                           s 
                         
                       
                       k 
                     
                      
                     
                         
                     
                      
                     
                       
                         P 
                          
                         
                           ( 
                           
                             X 
                             = 
                             n 
                           
                           ) 
                         
                       
                       . 
                     
                   
                 
               
               
                 
                   ( 
                   2 
                   ) 
                 
               
             
           
         
       
     
         [0063]    In some implementations, the connections between each of the proteins in the protein network can be weighted. For example, the connections made by known seed proteins may be given a higher weight when compared to the seed proteins that are added to the seed protein list (e.g., the seed proteins revealed by the methods described herein). In some implementations, the connections by seed proteins may be given a higher weight when compared to the connections made by non-seed proteins. By considering links to proteins with higher weights to be stronger, the direct neighbors of seed proteins have a higher chance of being identified as part of the disease cluster. Equation 1 can be modified to account for the weights, giving the below equation: 
         [0000]    
       
         
           
             
               
                 
                   
                     P 
                      
                     
                       ( 
                       
                         X 
                         = 
                         
                           k 
                           s 
                         
                       
                       ) 
                     
                   
                   = 
                   
                     
                       
                         
                           ( 
                           
                             
                               
                                 
                                   α 
                                   s 
                                 
                               
                             
                             
                               
                                 
                                   α 
                                    
                                   
                                       
                                   
                                    
                                   
                                     k 
                                     s 
                                   
                                 
                               
                             
                           
                           ) 
                         
                          
                         
                           ( 
                           
                             
                               
                                 
                                   N 
                                   - 
                                   s 
                                 
                               
                             
                             
                               
                                 
                                   k 
                                   - 
                                   
                                     k 
                                     s 
                                   
                                 
                               
                             
                           
                           ) 
                         
                       
                       
                         ( 
                         
                           
                             
                               
                                 N 
                                 + 
                                 
                                   
                                     ( 
                                     
                                       α 
                                       - 
                                       1 
                                     
                                     ) 
                                   
                                    
                                   
                                     k 
                                     s 
                                   
                                 
                               
                             
                           
                           
                             
                               
                                 k 
                                 + 
                                 
                                   
                                     ( 
                                     
                                       α 
                                       - 
                                       1 
                                     
                                     ) 
                                   
                                    
                                   
                                     k 
                                     s 
                                   
                                 
                               
                             
                           
                         
                         ) 
                       
                     
                     . 
                   
                 
               
               
                 
                   ( 
                   3 
                   ) 
                 
               
             
           
         
       
     
         [0064]    In equation 3, a is the weight of the specific protein connection. In some implementations, α for a seed protein can be set between 1 and 20 or between about 5 and 15, where α can be 1 for a non-seed protein. 
         [0065]    In some implementations, calculating the p-values can be computationally intensive. In some implementations, the connectivity factor for the proteins can be ranked directly without calculating the p-values for the proteins. In these implementations, proteins with the same k or k s  values can be ranked based on the respective k or k s  value. For example, if two candidate proteins have the same k, the candidate protein with the higher k s  will have fewer terms in equation 2, which results in a lower p-value. 
         [0066]    At step  310 , each of the connectivity factors are ranked. In some implementations, the connectivity factors are ranked from lowest p-value to highest p-value. A low p-value can indicate that the probability that the protein is connected to the seed protein by chance is low. Referring to  FIG. 4 , the p-values for each of the candidate proteins  406  are listed. 
         [0067]    At step  312 , the list of the plurality of seed proteins is updated responsive to the ranking of the candidate proteins from step  310 . In some implementations, each of the candidate proteins with a p-value less than a predetermined number may be added to the list of seed proteins. For example, each candidate protein with a p-value less that 0.05 may be added to the list of seed proteins. In some implementations, the candidate protein with the smallest p-value can be added to the list of seed proteins. In the example protein network  400  illustrated in  FIG. 4 , candidate protein  407  has the lowest p-value, with a p-value of 0.07.  FIG. 5  illustrates the protein network  400  at the end of the first iteration. As illustrated, protein candidate  407  has been added to the list of seed proteins. Accordingly, this information may also be reflected within the seed protein array  204  and the disease cluster array  206 . For example, a flag indicating that the protein represented by protein  407  is part of the disease cluster may be set and an indication of protein  407  may be added to the list of seed proteins stored in the seed protein array  204 . When the protein  407  is added to the seed protein array  204 , the s and the k s  from equation 1 may be appropriately updated. For example, s may be incremented by 1 for the next iteration (s→s+1). 
         [0068]    The system may then determine if a criterion is met (step  314 ). If the criterion is met the method  300  may proceed to step  316 . If the criterion is not met the method  300  may return to step  306 . In some implementations, the criterion is a predetermined number of iterations. For example, the method  300  may repeat between about 100 times and about 500 times or between about 150 times and about 350 times. In some implementations, the criterion is that no p-value is less than a predetermined threshold. For example, the method  300  may loop until no p-values are less than 0.01. In some implementations, the method may continue until every protein within the protein network is part of the disease cluster (or has been added to the seed protein list). In these implementations, the output of the method described herein may be a ranked list of each of the proteins in the protein network that indicates the likelihood that each of the proteins belongs to the disease cluster. 
         [0069]      FIG. 6  illustrates the protein network  400  during a second iteration of the method  300 . As described above, protein  407  is added to the seed protein list and the method  300  is repeated. During the second iteration of the method  300 , protein  408  is included in the list of candidate proteins because protein  408  is connected with protein  407 , which is now indicated as a seed protein because it had the lowest p-value in the last iteration. The connectivity factors for each of the new candidate proteins are calculated and then ranked. During the second iteration one or more of the new candidate proteins may be added to the list of seed proteins. 
         [0070]    At step  316 , responsive to the criterion being met, an indication of the proteins associated with the disease is provided. In some implementations, the indication can be provided to a user in a graphical format, for example as a protein network topology.  FIG. 7  illustrates an example output of the method  300 . The output protein network  700  indicates the original disease cluster  701 , which can correspond to the originally received seed proteins. The output protein network  700  can also indicate the proteins that were added to the seed protein list. The original seed proteins plus the added seed proteins can represent the disease cluster  702 . In some implementations, the indication of the proteins associated with the disease is output in as a data file. For example, the data file may be a data file similar to the data files that contained the original protein network data and seed protein data. The data to generate the indication of the disease cluster can come from the seed protein array, the disease cluster array, or a combination thereof. 
         [0071]    The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Modifications and variations can be made without departing from its spirit and scope of this disclosure. Functionally equivalent methods and apparatuses may exist within the scope of this disclosure. Such modifications and variations are intended to fall within the scope of the appended claims. The subject matter of the present disclosure includes the full scope of equivalents to which it is entitled. This disclosure is not limited to particular methods, reagents, compounds compositions or biological systems, which can vary. The terminology used herein is for the purpose of describing particular embodiments, and is not intended to be limiting. 
         [0072]    With respect to the use of substantially any plural or singular terms herein, the plural can include the singular or the singular can include the plural as is appropriate to the context or application. 
         [0073]    In general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). Claims directed toward the described subject matter may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, such recitation can mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). Any disjunctive word or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, can contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” includes the possibilities of “A” or “B” or “A and B.” 
         [0074]    In addition, where features or aspects of the disclosure are described in terms of Markush groups, the disclosure is also described in terms of any individual member or subgroup of members of the Markush group. 
         [0075]    Any ranges disclosed herein also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. Language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, a range includes each individual member. 
         [0076]    One or more or any part thereof of the techniques described herein can be implemented in computer hardware or software, or a combination of both. The methods can be implemented in computer programs using standard programming techniques following the method and figures described herein. Program code is applied to input data to perform the functions described herein and generate output information. The output information is applied to one or more output devices such as a display monitor. Each program may be implemented in a high level procedural or object oriented programming language to communicate with a computer system. However, the programs can be implemented in assembly or machine language, if desired. In any case, the language can be a compiled or interpreted language. Moreover, the program can run on dedicated integrated circuits preprogrammed for that purpose. 
         [0077]    Each such computer program can be stored on a storage medium or device (e.g., ROM or magnetic diskette) readable by a general or special purpose programmable computer, for configuring and operating the computer when the storage media or device is read by the computer to perform the procedures described herein. The computer program can also reside in cache or main memory during program execution. The analysis, preprocessing, and other methods described herein can also be implemented as a computer-readable storage medium, configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein. In some embodiments, the computer readable media is tangible and substantially non-transitory in nature, e.g., such that the recorded information is recorded in a form other than solely as a propagating signal. 
         [0078]    In some embodiments, a program product may include a signal bearing medium. The signal bearing medium may include one or more instructions that, when executed by, for example, a processor, may provide the functionality described above. In some implementations, signal bearing medium may encompass a computer-readable medium, such as, but not limited to, a hard disk drive, a Compact Disc (CD), a Digital Video Disk (DVD), a digital tape, memory, etc. In some implementations, the signal bearing medium may encompass a recordable medium, such as, but not limited to, memory, read/write (R/W) CDs, R/W DVDs, etc. In some implementations, signal bearing medium may encompass a communications medium such as, but not limited to, a digital or an analog communication medium (e.g., a fiber optic cable, a waveguide, a wired communications link, a wireless communication link, etc.). Thus, for example, the program product may be conveyed by an RF signal bearing medium, where the signal bearing medium is conveyed by a wireless communications medium (e.g., a wireless communications medium conforming with the IEEE 802.11 standard). 
         [0079]    Any of the signals and signal processing techniques may be digital or analog in nature, or combinations thereof. 
         [0080]    While certain embodiments of this disclosure have been particularly shown and described with references to preferred embodiments thereof, various changes in form and details may be made therein without departing from the scope of the disclosure.