Clinically intelligent diagnostic devices and methods

• US 20060240453A1
• Filed: 03/08/2006
• Published: 10/26/2006
• Est. Priority Date: 11/27/2000
• Status: Active Grant

• Current Assignee: Intelligent Medical Devices, Inc.
• Original Assignee: Intelligent Medical Devices, Inc.
• Inventors: Nikolic, Boris, Jacobs, Alice A., Gupta, Vineet
• Granted Patent: US 7,566,533 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: B01F 33/3036 using a biological motor, i.e. biological molecules which are activated and movement is induced to stir a fluid
• CPC Class Codes: B01F 33/45 Magnetic mixers; Mixers with magnetically driven stirrers
• CPC Class Codes: B01F 33/451 wherein the mixture is directly exposed to an electromagnetic field without use of a stirrer, e.g. for material comprising ferromagnetic particles or for molten metal
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00315 Microtiter plates
• CPC Class Codes: B01J 2219/00317 Microwell devices, i.e. having large numbers of wells
• CPC Class Codes: B01J 2219/00481 by the use of moving stirrers within the reaction vessels
• CPC Class Codes: B01J 2219/00497 Features relating to the solid phase supports
• CPC Class Codes: B01J 2219/00509 Microcolumns
• CPC Class Codes: B01J 2219/00511 Walls of reactor vessels
• CPC Class Codes: B01J 2219/00527 Sheets
• CPC Class Codes: B01J 2219/00547 Bar codes
• CPC Class Codes: B01J 2219/00585 Parallel processes
• CPC Class Codes: B01J 2219/00596 Solid-phase processes
• CPC Class Codes: B01J 2219/00605 the compounds being directly bound or immobilised to solid supports
• CPC Class Codes: B01J 2219/0061 The surface being organic
• CPC Class Codes: B01J 2219/00612 the surface being inorganic
• CPC Class Codes: B01J 2219/00619 using hydrophilic or hydrophobic regions
• CPC Class Codes: B01J 2219/00621 by physical means, e.g. trenches, raised areas
• CPC Class Codes: B01J 2219/00626 Covalent
• CPC Class Codes: B01J 2219/0063 : Other, e.g. van der Waals forces, hydrogen bonding
• CPC Class Codes: B01J 2219/00637 : by coating it with another layer
• CPC Class Codes: B01J 2219/00644 : the porous medium being present in discrete locations, e.g. gel pads
• CPC Class Codes: B01J 2219/00659 : Two-dimensional arrays
• CPC Class Codes: B01J 2219/00662 : Two-dimensional arrays within two-dimensional arrays
• CPC Class Codes: B01J 2219/00664 : Three-dimensional arrays
• CPC Class Codes: B01J 2219/00677 : Ex-situ synthesis followed by deposition on the substrate
• CPC Class Codes: B01J 2219/00689 : using computers
• CPC Class Codes: B01J 2219/00702 : Processes involving means for analysing and characterising the products
• CPC Class Codes: B01J 2219/0072 : Organic compounds
• CPC Class Codes: B01J 2219/00722 : Nucleotides
• CPC Class Codes: B01J 2219/00725 : Peptides
• CPC Class Codes: B01J 2219/00731 : Saccharides
• CPC Class Codes: B01J 2219/0074 : Biological products
• CPC Class Codes: B01J 2219/00745 : Inorganic compounds
• CPC Class Codes: B01L 2300/021 : Identification, e.g. bar codes
• CPC Class Codes: B01L 2300/0636 : Integrated biosensor, microarrays
• CPC Class Codes: B01L 2300/069 : Absorbents; Gels to retain a fluid
• CPC Class Codes: B01L 2300/0819 : Microarrays; Biochips
• CPC Class Codes: B01L 2300/0864 : comprising only one inlet and multiple receiving wells, e.g. for separation, splitting
• CPC Class Codes: B01L 3/5027 : by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip B01L3/5023 takes precedence; micromixers B01F33/30; microreactors for synthesis B01J19/0093; microcapillary devices in general B81B1/00
• CPC Class Codes: B01L 3/5085 : for multiple samples, e.g. microtitration plates
• CPC Class Codes: B01L 3/50857 : using arrays or bundles of open capillaries for holding samples
• CPC Class Codes: B82Y 30/00 : Nanotechnology for materials or surface science, e.g. nanocomposites
• CPC Class Codes: C12Q 1/6837 : using probe arrays or probe chips C12Q1/6874 takes precedence
• CPC Class Codes: C40B 40/06 : Libraries containing nucleotides or polynucleotides, or derivatives thereof
• CPC Class Codes: C40B 40/10 : Libraries containing peptides or polypeptides, or derivatives thereof
• CPC Class Codes: C40B 40/12 : Libraries containing saccharides or polysaccharides, or derivatives thereof
• CPC Class Codes: C40B 40/18 : Libraries containing only inorganic compounds or inorganic materials
• CPC Class Codes: C40B 60/14 : for creating libraries
• CPC Class Codes: C40B 70/00 : Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• CPC Class Codes: G01N 33/53 : Immunoassay; Biospecific binding assay; Materials therefor
• CPC Class Codes: G01N 33/543 : with an insoluble carrier for immobilising immunochemicals
• CPC Class Codes: G01N 33/54366 : Apparatus specially adapted for solid-phase testing
• CPC Class Codes: G01N 33/6803 : General methods of protein analysis not limited to specific proteins or families of proteins
• CPC Class Codes: G01N 33/6845 : Methods of identifying protein-protein interactions in protein mixtures

Abstract

The invention relates to the clinically intelligent design of diagnostic devices (such as microarrays) and methods of making and using such devices in differential diagnoses of specific clinical symptoms or sets of symptoms. In one aspect, the devices include various probes used to perform parallel screening of a number of analytes. The probes are clustered on the devices based on known clinical presentations of symptoms associated with specific diseases and disorders.

Claims

1-34. -34. (canceled)

35. An array comprising a plurality of probes that interact with at least one target in a sample, wherein the at least one target is associated with a cause of at least one symptom, the array comprising:

(a) a plurality of first probes for at least one target, wherein the target causes at least one symptom; and

(b) a plurality of second probes for at least one genetic marker and/or molecule that cause the at least one symptom.

36. The array according to claim 35, wherein the cause is selected from the group consisting of a pathogen, an infection, inflammation, autoimmunity, a neoplasm, and a drug.

37. The array according to claim 35, wherein the cause is iatrogenic, congenital, developmental, inherited, environmental, endocrine, and/or metabolic.

38. The array according to claim 35, wherein the target comprises a marker for a pathogen.

39. The array according to claim 38, wherein the pathogen is selected from the group consisting of bacteria, viruses, fungi, mycoplasma, protozoa, chlamidia, rickettsia, and algae.

40. The array according to claim 35, wherein the target is a nucleic acid selected from the group consisting of a DNA, an RNA, a PNA, and a combination and a chimera thereof.

41. The array according to claim 35, wherein the target is selected from the group consisting of an antibody, an antigen, an enzyme, and a cell.

42. The array according to claim 35, wherein the target is selected from the group consisting of a peptide, a polypeptide, a protein, a hapten, a glycoprotein, an aptamer, a small organic molecule, an inorganic molecule, a toxin, and a polysaccharide, or a combination thereof.

43. The array according to claim 42, wherein the polypeptide is selected from the group consisting of a zinc-finger binding protein, a minor-groove binder, a transcription factor, a helix-turn-helix motif, an immunoglobulin motif protein, a polyamide, an oligomeric heterocyclic minor groove binder, and a combination and chimera thereof.

44. The array according to claim 35, wherein the genetic marker is a marker in the pathogen.

45. The array according to claim 35, wherein the genetic marker is a marker in the subject.

46. The array according to claim 35, wherein the probe is selected from the group consisting of an antibody, an antigen, a protein, and a nucleic acid.

47. The array according to claim 35, wherein the plurality of probes allows parallel screening of a plurality of analytes.

48. The array according to claim 35, wherein the plurality of probes detects the absence of a target and/or genetic marker.

49. The array according to claim 35, wherein the sample is a biological sample.

50. The array according to claim 35, wherein the sample is selected from the group consisting of blood, cerebrospinal fluid, urine, sweat, a swab, a buccal swab, a tissue, a cell sample, and a cell culture.

51. The array according to claim 35, wherein the subject is a human.

52. The array according to claim 35, wherein the subject is an animal selected from the group consisting of a bird, a dog, a cat, a cow, a pig, and a horse.

53. The array according to claim 35, wherein the probe is attached to a surface.

54. The array according to claim 35, wherein the array is deposited on a microfluidic device.

55. The array according to claim 35, wherein the array is deposited on a sequencing chip.

56. The array according to claim 35, wherein the array is deposited on a biochip.

57. The array according to claim 35, wherein the array is deposited on a microarray.

58. The array according to claim 35, wherein the array is deposited on a multiplexed device.

59. The array according to claim 35, wherein the array is deposited on a bead.

60. The array according to claim 35, wherein the array is deposited on a membrane comprising a material selected from the group consisting of nitrocellulose, nylon, polyethylene, polycarbonate, glass microfiber, and gortex.

61. The array according to claim 35, wherein the array is deposited on a surface comprising a plurality of wells.

93. A method of manufacturing an array according to claim 35, the method comprising the steps of:

(a) binding to a surface a first plurality of probes for one or more infectious agents that cause one or more medical symptoms;

(b) binding to the surface a second plurality of probes for one or more genetic markers that cause the one or more medical symptoms; and

(c) removing any unbound probes.

62. A kit comprising

(a) an array comprising

(i) a plurality of first probes for at least one target in a sample, wherein the target causes at least one symptom, and

(ii) a plurality of second probes for at least one genetic marker that causes the at least one symptom;

and

(b) reagents and/or materials necessary for testing the sample.

63. The kit according to claim 62, wherein the plurality of first and second probes detects at least one target associated with jaundice and/or liver failure.

64. The kit according to claim 63, wherein the plurality of first probes detects at least five targets selected from the group consisting of anti-LKM-1 antibodies, anti-mitochondrial M2 antibodies, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis D virus, Hepatitis E virus, and CMV virus.

65. The kit according to claim 62, wherein the plurality of second probes detects at least one of a mutation and/or allelic variant of the subject selected from the group consisting of Dubin-Johnson Syndrome, Hyperbilirubinemia Type I, Acute Hepatic Porphyria, Delta-Aminolevulinate Dehydratase Deficiency, Porphobilinogen Synthase Deficiency, Alagille Syndrome, Arteriohepatic Dysplasia, Cholestasis with Peripheral Pulmonary Stenosis, Alpha-1-Antitrypsin Deficiency, Carbamoylphosphate Synthetase I Deficiency, Carbamyl Phosphatase Deficiency, Carbamyl Phosphate Synthetase Deficiency, Carnitine-Acylcarmitine Translocase Deficiency, Citrullinemia, Ferrochelatase Deficiency, Heme Synthetase Deficiency, Fatty Acid Oxidation Disorder, Unspecified, Fructose 1,6 Bisphosphatase Deficiency, Galactosemia, Galactose Epimerase Deficiency, Galactose-1-Phosphate Uridyltransferase Deficiency, NGlutaricacidemia Type II, Glutaricaciduria Type II, Glycogen Storage Disease Type I/Ia, Glucose-6-Phosphatase Deficiency, Von Gierke Disease, Glycogen Storage Disease Type III, Cori Disease, Debrancher Deficiency, Forbe Disease, Glycogen Storage Disease Type IV, Brancher Deficiency, Glycogen Storage Disease Type IX, Glycogen Storage Disease Type VIII, Phosphorylase Kinase Deficiency of Liver, Glycogen Storage Disease Type Ib, Glucose-6-Phosphate Translocase Defect, Glycogen Storage Disease Type VI, HERS Disease, Hereditary Coproporphyria, Coproporphyrinogen Oxidase Deficiency, Harderoporphyria, Hereditary Fructose Intolerance, Fructosemia, Hereditary Hemochromatosis, Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency, Acute Fatty Liver, Disease of Pregnancy, HELLP, Hemolysis, Enzymes, and Low Platelets, LCHAD Deficiency, Trifunctional Protein Deficiency, Long Chain Acyl-CoA Dehydrogenase Deficiency, LCAD Deficiency, Medium Chain 3-Ketothiolase Deficiency, MCKAT Deficiency, Medium Chain Acyl-Coenzyme A Dehydrogenase Deficiency, MCAD Deficiency, Mucopolysaccharidosis Type II, Hunter Syndrome, MPS II, Mucopolysaccharidosis Type IIIB, MPS IIIB, Sanfilippo Syndrome Type B, Mucopolysaccharidosis Type IIIC, MPS IIIC, Sanfilippo Syndrome Type C, Mucopolysaccharidosis Type IVB, MPS IVB, Morquio Syndrome Type B, Mucopolysaccharidosis Type VI, Arylsulfatase B Deficiency, MPS VI, Maroteaux, Lamy Syndrome, Mucopolysaccharidosis Type VII, Glucuronidase Deficiency MPS, MPS VII, Sly Syndrome, Niemann-Pick Disease Without Sphingomyelinase Deficiency, Niemann-Pick Disease Type C, Niemann-Pick Disease Type D, Niemann-Pick Disease, Nova Scotian Type, Ornithine Transcarbamylase Deficiency, OTC Deficiency, Phosphorylase Kinase Deficiency of Liver and Muscle, Polycystic Kidney Disease, Recessive, ARPKD, PKD, Infantile, PKD, Recessive, Salla Disease, Sialic Acid Storage Disease, Sialidosis, Glycoprotein Neuramimidase Deficiency, ML I, ML1, Mucolipidosis, Wilson Disease, Wolman Disease, Cholesterol Ester Storage Disease, and/or Zellweger syndrome, and Cerebrohepatorenal Syndrome.

66. The kit according to claim 62, wherein the plurality of first and second probes detects at least one target associated with pharyngitis.

67. The kit according to claim 66, wherein the plurality of first probes detects at least five targets selected from the group consisting of a virus, a bacteria, a mycoplasma, and an antibody to a pathogen.

68. The kit according to claim 67, wherein the virus is selected from the group consisting of Rhinovirus, Coronavirus, Adenovirus types 3, 4, 7, and 14, Herpes simplex virus types 1 and 2, Parainfluenza virus types 1-4, Influenza virus types A and B, Coxsackievirus A types 2, 4-6, 8, and 10, Epstein-Barr virus, Cytomegalovirus, and HIV-1.

69. The kit according to claim 67, wherein the bacteria is selected from the group consisting of Streptococcus pyogenes (group A beta-hemolytic streptococci), Group C beta-hemolytic streptococci, Neisseria gonorrhoeae, Corynebacterium diphtheriae, Corynebacterium ulcerans, Arcanobacterium haemolyticum (Corynebacterium haemolyticum), Yersinia enterocolitica, Treponema pallidum, and Chlamydia pneumoniae.

70. The kit according to claim 67, wherein the mycoplasma is selected from the group consisting of Mycoplasma pneumoniae and Mycoplasma hominis (type 1).

71. The kit according to claim 67, wherein the antibody is selected from the group consisting of an antibody to beta-hemolytic Lancefield group A Streptococcus, Antideoxyribonuclease-B, and Antistreptolysin-O.

72. The kit according to claim 62, wherein the plurality of first and second probes detects at least one target associated with lower respiratory tract symptoms.

73. The kit according to claim 72, wherein the lower respiratory tract symptoms are selected from the group consisting of cough, fever, chest discomfort, dyspnea, pneumonia, and a combination thereof.

74. The kit according to claim 72, wherein the plurality of first and second probes detects causative agents related to biological warfare or terrorism.

75. The kit according to claim 72, wherein the plurality of first probes detects at least five targets selected from the group consisting of bacteria, mycoplasma, viruses, chlamydiae, rickettsiae, fungi, and parasites.

76. The kit according to claim 75, wherein the bacteria is selected from the group consisting of Streptococcus pneumoniae, Staphylococcus aureus, Group A streptococci, Haemophilus influenzae, Klebsiella pneumoniae, Proteus mirabilis, E. Coli, Pseudomonas aeruginosa, Moraxella (Branhamella)catarrhalis;

Legionella pneumophila;

Porphyromonas gingivalis;

Prevotella melaminogenica, Fusobacterium nucleatum, Actinomyces spp., Spirochetes, Anaerobic streptococci, Fusobacteria, Bacillus anthracis, Yersinia pestis, Francisells tularensis, Coxiella burnetti, and Yersinia enterocolitica.

77. The kit according to claim 75, wherein the mycoplasma is selected from the group consisting of Mycoplasma pneumoniae and Mycobacterium tuberculosis.

78. The kit according to claim 75, wherein the virus is selected from the group consisting of Influenza A, Influenza B, Adenovirus, Respiratory Syncytial Virus, Parainfluenza virus, Cytomegalovirus, Varicella-zoster virus, Variola major (small pox), Rubeola, Blastomyces spp., Chlamydia psittaci, Coxiella burnetii, Aspergillus, Noccardia, Candida, Pneumocystis Carinii, Histoplasmosis, and Coccidiodomycosis.

79. The kit according to claim 62, wherein the plurality of first and second probes detects at least one target associated with headache, fever, meningismus, nausea, vomiting, rigors, profuse sweating, weakness, myalgias, and/or photophobia.

80. The kit according to claim 79, wherein the plurality of first and second probes detects at least five targets selected from the group consisting of infectious markers, genetic markers, and therapeutic markers.

81. The kit according to claim 80, wherein the infectious markers are selected from the group consisting of Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, Listeria monocytogenes, Streptococcus agalactiae, Propionibacterium acnes, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella spp., Nocardia spp., Mycobacterium tuberculosis, Spirochetes (such as Treponema pallidum (syphilis), Borrelia Burgdorferi (Lyme diseases, Leptospira spp.), and Rickettsiae (such as Rickettsia rickettsii (Rocky Mountain spotted fever), Rickettsia conorii, Rickettsia prowazekii (epidemic or louse-borne typhus), Rickettsia typhi (endemic or murine typhus), Rickettsia tsutsugamushi (scrub typhus), Ehrlichia spp.);

Nonpolio enteroviruses (echovirus 11;

echovirus 9;

coxsackievirus B5;

echoviruses 30, 4, and 6;

coxsackieviruses B2, B4, B3, and A9;

echoviruses 3, 7, 5, and 21; and

coxsackievirus B1, enteroviruses 70 and

     71);

Mumps virus;

Arboviruses (Flaviviridae, The mosquito-borne California enc. Virus, St. Louis enc. Virus, Eastern equine enc. Virus, Western equine enc. Virus, Venezuelan equine encephalitis viruses and Tick-borne Colorado tick fever);

Herpesviruses (Primarily herpes simplex virus type 2, but also herpes simplex virus type 1, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpesvirus

     6);

Lymphocytic choriomeningitis virus;

Human immunodeficiency virus;

Adenovirus;

Parainfluenza virus types 2 and 3;

Influenza virus;

Measles virus; and

Polio virus.

82. The kit according to claim 80, wherein the genetic marker is selected from the group consisting of C5, C6, C7, C8, C9, and Properidin.

83. The kit according to claim 80, wherein the therapeutic marker is beta-lactamase.

84. The kit according to claim 62, wherein the plurality of first and second probes detects at least one target associated with diarrhea.

85. The kit according to claim 84, wherein the plurality of first and second probes detects at least five targets selected from the group consisting of bacteria, viruses, pathogens, genetic factors, autoimmune disease, chemical agents, and therapeutic markers.

86. The kit according to claim 85, wherein the bacteria is selected from the group consisting of Bacillus cereus, Staphylococcus aureus, Clostridium perfringens, Vibrio cholerae, enterotoxigenic Escheria coli, Klebsiella pneumoniae, Aeromonas species, Enteropathogenic and enteroadherent E. coli (O157:

H7), Giardia organisms, Clostridium difficile, Hemorrhagic E. coli, Salmonella, Campylobacter, Aeromonas species, Vibrio parahaemolyticus, Yersinia, Shigella species, enteroinvasive E. coli, Bacillus anthracis, and Clostridium botulinum.

87. The kit according to claim 85, wherein the virus is selected from the group consisting of Cytomegalovirus, Herpes simplex, Enteropathogenic Adenovirus, Rotovirus (Group A, B, C), Calicivirus, Astrovirus, Cryptosporidium, Septata intestinalis, Microsporidium_—

Entercytozoon bienusi, Isospora belli, Cyclospora species, Giardia lamblia, Entamoeba histolytica, Leishmania donovani, Blastocystic hominis, Pneumocystis carini, Histoplasma, Coccidioides, Candida albicans, and Cryptococcus.

88. The kit according to claim 85, wherein the genetic disease is selected from the group consisting of Acute Hepatic Porphyria;

Delta-Aminolevulinate Dehydratase Deficiency;

Porphobilinogen Synthase Deficiency, Amyloidosis Type I;

Amyloid Polyneuropathy, Andrade or Portugese Type;

Amyloidosis, Portugese Type;

Amyloidosis, Swedish Type, Beckwith-Wiedemann Syndrome, Cystic Fibrosis;

CF, Dubin-Johnson Syndrome;

Hyperbilirubinemia Type II, Epidermolysis Bullosa Letalis with Pyloric Atresia;

Aplasia Cutis Congenita with Gastrointestinal Atresia;

Carmi Syndrome, Erythropoietic Protoporphyria;

Erythrohepatic Protoporphyria;

Ferrochelatase Deficiency;

Heme Synthetase Deficiency Ethylmalonic Encephalopathy, Familial Adenomatous Polyposis;

APC;

Adenomatous Polyposis Coli;

FAP;

Gardner syndrome, Familial Dysautonomia;

Riley-Day Syndrome, Familial Gastric Cancer, Familial Hibernia Fever;

Familial Periodic Fever;

TRAPS, Familial Mediterranean Fever;

Recurrent Polyserositis, Hereditary Coproporphyria;

Coproporphyrinogen Oxidase Deficiency;

Harderoporphyria (Included), Hereditary Non-Polyposis Colon Cancer;

HNPCC;

Lynch syndrome, Hermansky-Pudlak Syndrome;

HPS, Multiple Endocrine Neoplasia Typ;

MEN1, Ornithine Transcarbamylase Deficiency;

OTC Deficiency, Pearson Syndrome;

Sideroblastic Anemia w/Marrow Cell Vacuolization &

Exocrine Pancreatic Dysfxn, Peutz-Jeghers Syndrome;

Hamartomatous Intestinal Polyposis;

PJS, Phosphoglycerate Kinase Deficiency;

PGK Deficiency, Pseudoxanthoma Elasticum, Dominant;

PXE, Dominant Pseudoxanthoma Elasticum, Recessive;

PXE, Recessive Pyruvate Kinase Deficiency, Townes-Brocks Syndrome;

TBS, Wolman Disease;

Cholesterol Ester Storage Disease von Hippel-Lindau Syndrome; and

VHL.

89. The kit according to claim 85, wherein the chemical agent is selected from the group consisting of Adamsite (DM), Diphenylchloroarsine (DA), Diphenylcyanoarsine (DC).

90. The kit according to claim 85, wherein the therapeutic marker is beta-lactamase.

91. The kit according to claim 62, wherein the plurality of first and second probes detects at least one target associated with septicemia.

92. The kit according to claim 91, wherein the plurality of first and second probes detects at least five targets selected from the group consisting of elevated temperature, tachycardia, increased respirations, leukocytosis, impaired peripheral leukocyte response, and oliguria.