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(12) United States Patent (10) Patent No.: US 7,219,016 B2 Rimm Et Al

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(12) United States Patent (10) Patent No.: US 7,219,016 B2 Rimm Et Al US007219016B2 (12) United States Patent (10) Patent No.: US 7,219,016 B2 Rimm et al. (45) Date of Patent: May 15, 2007 (54) SYSTEMS AND METHODS FOR 2003/003.6855 A1 2/2003 Harris et al. .................. 7O2/19 AUTOMATED ANALYSIS OF CELLS AND FOREIGN PATENT DOCUMENTS TSSUES WO WOOOf 24940 5, 2000 (75) Inventors: David L. Rimm, Branford, CT (US); WO WO 01/20044 3, 2001 Robert L. Camp, Stamford, CT (US) WO WO O1/22086 3, 2001 (73) Assignee: Yale University, New Haven, CT (US) OTHER PUBLICATIONS Rigaut et al. “Three-Dimensional DNA Image Cytometry by Confo (*) Notice: Subject to any disclaimer, the term of this cal Scanning Laser Microscopy in ThickTissue Blocks,” Cytometry patent is extended or adjusted under 35 (1991) vol. 12, pp. 511-524.* U.S.C. 154(b) by 770 days. Staines et al. “Three-Color Immunofluorescence Histochemistry Allowing Triple Labeling Within a Single Section.” The Journal of (21) Appl. No.: 10/062,308 Histochemistry145-151. and Cytochemistry (1988) vol. 36, No. 6, pp. 1-1. Wood et al. "B-Spectrin is Colocalized with Both Voltage-gated (22) Filed: Feb. 1, 2002 Sodium Channels and Ankyring at the Adult Rat Neuromuscular (65) Prior Publication Data Junction.”E. Thee Journal of Cell BiologyBiol ( 1988)) vovol. 140, No.O. 3,5, pppp. US 20O2/O177149 A1 Nov. 28, 2002 Forus et al. “Sensitive Fluorescent in situ Hybridisation Method for s the Characterisation of Breast Cancer Cells in Bone Marrow Aspi Related U.S. Application Data rates.” The Journal of Clinical Pathology (1999) vol. 52, pp. 68-74.* Zhou et al., “A Multiple Wavelength Algorithm in Color Image (60) Provisional application No. 60/334,723, filed on Oct. Analysis and Its Applications in Stain Decomposition in Micros 31, 2001, provisional application No. 60/285,155, copy Images.” Med. Phys. 23(12): 1977-1986 (1996). filed on Apr. 20, 2001. Arnold and Chapham; "Molecular Determinants for Subcellular Localization of PSD-9 with an Interacting K+ Channel”. Neuron 23: (51) Int. Cl. 149-157 (May 1999). GOIN 33/48 (2006.01) cDNAChen et Microarray al.; Ratio:Based Images”. Decisions Journal ofand Biochemical the Quantative Optics analysis 2(4): (52) U.S. Cl. ....................... 702/19, 382/133; 435/721: 364-374, (Oct. 1997). 348/8O Klein and Aguzzi: "The Neuroimmune Interface In Prion Diseases”. (58) Field of Classification Search .................. 702/19, News Physiol. Sci. 15: 250-255, (Oct. 2000). 435/6 * cited by examiner See application file for complete search history. y Primary Examiner Michael Borin (56) References Cited Assistant Examiner Jerry Lin U.S. PATENT DOCUMENTS (74) Attorney, Agent, or Firm—John P. White, Esq.; Cooper & Dunham LLP 4,998.284 A 3, 1991 Bacus et al. ................ 382,133 5,784,162 A 7/1998 Cabib et al. ................ 356,456 (57) ABSTRACT 5,989,835 A 11/1999 Dunlay et al. ............... 435/72 6,165,734. A 12/2000 Garini et al. ... ... 435,721 Systems and methods for rapidly analyzing cell containing 6,229,649 B1 5/2001 Woods et al. ............... 359,560 samples, for example to identify morphology or to localize 6,337,472 B1 1/2002 Garner et al. ............ 250/2013 ples, I mp morpnology 6,466,690 B2 10/2002 Bacus et al. ................ and quantitate biomarkers are disclosed. 6,727,071 B1 * 4/2004 Dunlay et al. .. ... 435/721 2002fOO67409 A1* 6/2002 Harari et al. ................. 348.80 14 Claims, 6 Drawing Sheets U.S. Patent May 15, 2007 Sheet 1 of 6 US 7.219,016 B2 Fique 1 U.S. Patent May 15, 2007 Sheet 2 of 6 US 7.219,016 B2 s E 275 R 53 225 175 e 25 S. 75 s 25 S S 25 7s 125 17s. 225 275 C Pathologist-based score - Array 1 Pathologist-based Score - Array 1 Automated - a Top 25% - Bottom 25% p = 0.0003 Pathologist based - a Top 25% - Bottom 25% p = 0.0020 3 5 7 Automated Score - Array f (x100) Figure 7. U.S. Patent May 15, 2007 Sheet 3 of 6 US 7.219,016 B2 B1 Remove atypically sized spots B2 Scan image with mask B3 Determine where mask Covers area with highest average pixel intensity B4 Set pixel intensity to zero in area 40 entire image processed ldentify reference points in identified B5 histoCores B6 Connect reference points of identified Define coordinates for reference points B7 and interSections between Connections FIG. 3 U.S. Patent May 15, 2007 Sheet 4 of 6 US 7.219,016 B2 C1 develop mask C2 mask locale and signal images C3 remove out-of-focus information (e.g., using pseudo-deconvolution) & C4 assign pixels to locales C5 map locales onto signal image FIG. 4 U.S. Patent May 15, 2007 Sheet S of 6 US 7.219,016 B2 1 / O / O C /2-O OOOOOOOOOOOOOC OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO /3o OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO O OC O OOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO OOOOOOOOOOOOOO F.G. 5 U.S. Patent May 15, 2007 Sheet 6 of 6 US 7.219,016 B2 s US 7,219,016 B2 1. 2 SYSTEMIS AND METHODS FOR particularly at the low and high ends of the scale, as well as AUTOMATED ANALYSIS OF CELLS AND the tendency to round scores (e.g. 50% at 3+ for a score of TISSUES 150, versus 47% at 3+ for a score of 141), limits the effectiveness of the H-score. Under 35 USC S 119(e)(1), this application claims the Automated systems and methods for rapidly analyzing benefit of prior U.S. provisional application 60/285,155, tissue, including tissue microarrays, that permit the identi filed Apr. 20, 2001, and U.S. provisional application 60/334, fication and localization of identified biomarkers within 723, filed Oct. 31, 2001, the contents of which are incorpo tissues and other cell containing samples, are needed. rated herein by reference. Work described herein was supported in part by grant No. 10 2. SUMMARY OF THE INVENTION 5K08ES011571 awarded by the National Institute of Health. The U.S. Government may therefore have certain rights in In one aspect, the invention features systems and methods the invention. for rapidly analyzing cell containing samples to localize and quantitate particular biomarkers within cells. In one embodi 1. BACKGROUND OF THE INVENTION 15 ment, the method is implemented by a computer and Super imposes an image of the biomarker against an image of a Tissue microarray technology offers the opportunity for user defined area within the cell to determine whether the high throughput analysis of tissue samples (Konen, J. et al., biomarker is within the user defined area. Nat. Med. 4:844–7 (1998); Kallioniemi, O. P. et al., Hum. Mol. Genet. 10:657–62 (2001); Rimm, D. L. et al., Cancer In another aspect, the invention features an algorithm that J. 7:24-31 (2001)). For example, the ability to rapidly facilitates the optical analysis of an array of biological perform large scale studies using tissue microarrays can samples, despite image irregularities, distortions, varying provide critical information for identifying and validating topologies, and the absence of one or more elements. drug targets/prognostic markers (e.g. estrogen receptor (ER) Analysis of patient samples according to the systems and and HER2/neu) and candidate therapeutics. 25 processes described herein can be useful diagnostically (e.g. Automated quantitative analysis of tissue samples in to identify patients who have a particular disease, have been microarrays, however, presents several challenges, includ exposed to a particular toxin or are responding well to a ing heterogeneity of tissue sections, Subcellular localization particular therapeutic or organ transplant) and prognostically of staining, and the presence of background signals. For (e.g. to identify patients who are likely to develop a par example, depending on the type of tumor or tissue section 30 ticular disease, respond well to a particular therapeutic or be being analyzed, the area of interest may represent nearly the accepting of a particular organ transplant). As new and better entire sample, or only a Small percentage. For instance, a markers of disease become identified in the post-genomic pancreatic carcinoma or lobular carcinoma of the breast with era, the instant described processes, which not only quanti Substantial desmoplastic response may show stromal tissue tate the markers, but also determine their relative location representing a large percentage of the total area. If the goal 35 within a cell, will increase in applicability. of the assay is to determine epithelial cell expression of a Automated analysis of cell containing preparations, as given marker, a protocol must be used that evaluates only described herein, can provide a rapid assessment of the that region. The protocol must not only be able to select the prognostic benefit of biomarkers. In addition, these auto region of interest but also normalize it, so that the expression mated techniques can identify associations that are typically level read from any given area can be compared with that of 40 not revealed using manual techniques. Also, automated other areas. Subcellular localization presents similar chal analysis can better discern Subtle differences in staining lenges. Comparisons of nuclear or membranous staining, for intensity, particularly at the upper and lower extremes. The example, are quite different from those in total cytoplasmic ability to detect low level expression and distinguish it from staining. no expression can provide important prognostic information. Certain methods (including confocal and convolution/ 45 Furthermore, analysis of the sub-cellular distribution of deconvolution microscopy) have been used to quantify certain biomarkers may elucidate previously unrecognized expression of proteins at the cellular (or sub-cellular) level associations with patient Survival.
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