# US 9,519,751 B2 · Systems and methods for detecting the presence of a biological status using clustering

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- Number: US 9,519,751 B2
- Document ID: US9519751B2
- Status: Granted
- Kind: B2
- Application number: 13/853,897
- Filed: 2013-03-29
- Published: 2013-08-01
- Granted: 2016-12-13
- Earliest claimed: 2009-11-13
- Assignees: Beckman Coulter, Inc.
- Applicants: Beckman Coulter, Inc.
- Inventors: Jiuliu Lu; Zihua Wang; Antonio Arevalo Reyes; Erik Alan Gustafson; John Steven Riley
- Web page: https://patentgrep.com/patent/US9519751B2

## CPC

- G16B 40/00: ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- C12Q 1/689: for bacteria
- G16B 5/00: ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G16B 20/00: ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
- C12Q 2600/112: Disease subtyping, staging or classification
- G16B 40/20: Supervised data analysis
- G16B 40/30: Unsupervised data analysis
- G16B: BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

A method for determining the presence of a biological entity. The method may include entering into a digital computer, at least a plurality of first input values associated with a first genetic element, a plurality of second input values associated with a second genetic element, and a plurality of third input values associated with a third genetic element associated with a plurality of samples. The method also includes determining a threshold value associated with the third genetic element, separating the samples using the threshold value into a first set of samples and a second set of samples, clustering the first set of samples in a feature space defined by the first genetic element and the second genetic element, defining a first boundary space using the first set of samples, and defining a second boundary space using the second set of samples.

## Claims

### Claim 1

A method of creating an analytical model, which differentiates a biological status from other biological statuses, the method comprising:
entering, into a digital computer, at least a plurality of first input values associated with a first genetic element, a plurality of second input values associated with a second genetic element, and a plurality of third input values associated with a third genetic element;
creating one or more intermediate values using at least the plurality of first input values associated with the first genetic element and at least the plurality of second input values associated with a second genetic element using the digital computer, wherein each intermediate value is a function of at least one or more first input values and at least one or more second input values; and
creating a boundary space for the biological status using the one or more intermediate values and the plurality of third input values using the digital computer,
wherein the boundary space differentiates the biological status from other biological statuses,
wherein the first genetic element comprises mecA, the second genetic element comprises a Staphylococcus aureus (SA)-target gene sequence, and the third genetic element comprises SCCmec, and wherein the biological status comprises an MRSA status.

### Claim 2 (depends on 1)

The method of claim 1 wherein the Staphylococcus aureus (SA)-target gene sequence comprises femA.

### Claim 3 (depends on 2)

The method of claim 2 wherein the intermediate value is defined by the equation:
intermediate value=mecA*sin(−0.3)+femA*cos(−0.3).

### Claim 4 (depends on 1)

The method of claim 1 wherein the boundary space is defined by an ellipse.

### Claim 5 (depends on 1)

The method of claim 1,
wherein the boundary space is defined by an ellipse, and wherein a cost function is used to optimize the ellipse.

### Claim 6 (depends on 1)

The method of claim 1,
wherein the plurality of first, second and third values are Ct values.

### Claim 7 (depends on 6)

A method for using an analytical model created according to the method of claim 6, wherein the method for using the analytical model comprises:
entering a first input value, second input value, and third input value associated with an unknown sample into the digital computer or other digital computer, wherein the first input value, the second input value and the third input value is associated with the first, second, and third genetic elements in the unknown sample; and
classifying the unknown sample as being associated with the biological status using the boundary space.

### Claim 8 (depends on 6)

A digital computer comprising a computer readable medium, and a processor coupled to the computer readable medium, the computer readable medium comprising code, executable by the processor to implement the method of claim 6.

### Claim 9 (depends on 8)

A system comprising a measuring module coupled to the digital computer of claim 8.

### Claim 10 (depends on 9)

The system of claim 9, wherein the measuring module is a real time PCR apparatus.

### Claim 11 (depends on 1)

The method of claim 1 further comprising, prior to entering:
subjecting the samples to conditions that will expose nucleic acids in the samples; and
amplifying and detecting the presence and amounts of at least the first genetic element, the second genetic element and the third genetic element.

### Claim 12 (depends on 1)

A method for using an analytical model created according to the method of claim 1, wherein the method for using the analytical model comprises:
entering a first input value, second input value, and third input value associated with an unknown sample into the digital computer or other digital computer, wherein the first input value, the second input value and the third input value is associated with the first, second, and third genetic elements in the unknown sample; and
classifying the unknown sample as being associated with the biological status using the boundary space.

### Claim 13 (depends on 1)

The method of claim 1 wherein a detection of an SCCmec/orfX junction indicates the presence of SCCmec.

### Claim 14 (depends on 1)

The method of claim 1 wherein SCCmec is at an orfX junction.

### Claim 15

A non-transitory computer readable medium comprising code executable by a processor, for implementing a method comprising:
entering, into a digital computer, at least a plurality of first input values associated with a first genetic element, a plurality of second input values associated with a second genetic element, and a plurality of third input values associated with a third genetic element;
creating one or more intermediate values using at least the plurality of first input values associated with the first genetic element and at least the plurality of second input values associated with a second genetic element using the digital computer, wherein each intermediate value is a function of at least one or more first input values and at least one or more second input values; and
creating a boundary space for the biological status using the one or more intermediate values and the plurality of third input values using the digital computer,
wherein the boundary space differentiates the biological status from other biological statuses,
wherein the first genetic element comprises mecA, the second genetic element comprises a Staphylococcus aureus (SA)-target gene sequence, and the third genetic element comprises SCCmec, and wherein the biological status comprises an MRSA status.

### Claim 16 (depends on 15)

A digital computer comprising the computer readable medium of claim 15, and a processor coupled to the computer readable medium.

### Claim 17 (depends on 16)

The digital computer of claim 16, further comprising a display coupled to the processor, wherein the method further comprises displaying the boundary space on the display.

### Claim 18 (depends on 16)

A system comprising a measuring module coupled to the digital computer of claim 16.

### Claim 19 (depends on 18)

The system of claim 18, wherein the measuring module is a real time PCR apparatus.

### Claim 20 (depends on 15)

The non-transitory computer readable medium of claim 15, wherein the Staphylococcus aureus (SA)-target gene sequence comprises femA.

### Claim 21 (depends on 15)

The non-transitory computer readable medium of claim 15,
wherein the plurality of first, second and third values are Ct values.