System for determining a health status of a tissue of interest

Abstract

The invention generally relates to methods for assessing the health of a tissue by characterizing circulating nucleic acids in a biological sample. According to certain embodiments, methods for assessing the health of a tissue include the steps of detecting a sample level of RNA in a biological sample, comparing the sample level of RNA to a reference level of RNA specific to the tissue, determining whether a difference exists between the sample level and the reference level, and characterizing the tissue as abnormal if a difference is detected.

What is claimed is: 
     
         1 . A method for determining that a pregnant subject or a fetus of said pregnant subject is at an elevated risk of a pregnancy-related health condition, comprising:
 (a) obtaining a biological sample from said pregnant subject;   (b) obtaining sequence information of nucleic acid molecules derived from said biological sample to identify a set of pregnancy-related markers in said biological sample; and   (c) using a programmed computer to deconvolve said set of pregnancy-related markers identified in (b) to determine tissue-specific contributions of one or more tissue types among said set of pregnancy-related markers, thereby determining that said pregnant subject or said fetus of said pregnant subject is at said elevated risk of said pregnancy-related health condition.   
     
     
         2 . The method of  claim 1 , wherein said biological sample is selected from the group consisting of a blood sample, serum sample, plasma sample, saliva sample, stool sample, sputum sample, urine sample, semen sample, transvaginal fluid sample, breast milk sample, breast fluid sample, breast nipple aspirate sample, cerebrospinal fluid sample, sweat sample, a cell biopsy sample, and a tissue biopsy sample. 
     
     
         3 . The method of  claim 2 , wherein said biological sample is a blood sample or a plasma sample. 
     
     
         4 . The method of  claim 1 , wherein said set of pregnancy-related markers comprises a set of ribonucleic acid (RNA) transcripts. 
     
     
         5 . The method of  claim 4 , wherein obtaining said sequence information of said nucleic acid molecules comprises reverse transcribing RNA molecules derived from said biological sample to produce complementary deoxyribonucleic acid (cDNA) molecules, and sequencing said cDNA molecules or derivatives thereof to identify said set of RNA transcripts. 
     
     
         6 . The method of  claim 5 , further comprising amplifying said cDNA molecules to produce amplified products, and sequencing said amplified products or derivatives thereof to identify said set of RNA transcripts. 
     
     
         7 . The method of  claim 1 , wherein said pregnancy-related health condition comprises pre-term birth. 
     
     
         8 . The method of  claim 7 , wherein said pre-term birth is indicated by pre-eclampsia. 
     
     
         9 . The method of  claim 1 , wherein said pregnancy-related health condition comprises pre-eclampsia. 
     
     
         10 . The method of  claim 1 , wherein said pregnancy-related health condition comprises one or more anomalies in pregnancy 
     
     
         11 . The method of  claim 1 , wherein said pregnancy-related health condition comprises one or more anomalies in fetal development. 
     
     
         12 . The method of  claim 1 , wherein said set of pregnancy-related markers comprises one or more markers corresponding to tissue-specific differentially expressed genes. 
     
     
         13 . The method of  claim 12 , wherein said one or more tissue-specific differentially expressed genes comprise one or more maternal-specific genes. 
     
     
         14 . The method of  claim 12 , wherein said one or more tissue-specific differentially expressed genes comprise one or more placental-specific genes. 
     
     
         15 . The method of  claim 12 , wherein said one or more tissue-specific differentially expressed genes comprise one or more fetal-specific genes. 
     
     
         16 . The method of  claim 15 , wherein said one or more fetal-specific genes comprise one or more genes corresponding to a fetal tissue type selected from the group consisting of: brain, liver, thymus, and lung. 
     
     
         17 . The method of  claim 1 , further comprising identifying a clinical intervention for said pregnant subject or said fetus of said pregnant subject based at least in part on said elevated risk of pregnancy-related health condition determined in (c). 
     
     
         18 . The method of  claim 17 , wherein said clinical intervention comprises a drug treatment. 
     
     
         19 . The method of  claim 1 , wherein said pregnant subject is in a first trimester of pregnancy. 
     
     
         20 . The method of  claim 1 , wherein said pregnant subject is in a second trimester of pregnancy. 
     
     
         21 . The method of  claim 1 , wherein said pregnant subject is in a third trimester of pregnancy. 
     
     
         22 . The method of  claim 1 , wherein deconvolving said set of pregnancy-related markers comprises comparing processing said set of pregnancy-related markers with a reference. 
     
     
         23 . The method of  claim 22 , wherein said reference corresponds to a set of pregnancy-related markers from one or more non-pregnant subjects or one or more pregnant subjects. 
     
     
         24 . The method of  claim 22 , wherein deconvolving said set of pregnancy-related markers comprises identifying a difference between said set of pregnancy-related markers and said reference, and using said difference to determine said elevated risk of said pregnancy-related health condition. 
     
     
         25 . The method of  claim 24 , further comprising determining a level of fold change in quantitative polymerase chain reaction (qPCR) measurements based at least in part on data corresponding to said set of pregnancy-related markers and said reference to identify said difference. 
     
     
         26 . The method of  claim 24 , further comprising performing principle component analysis on data corresponding to said set of pregnancy-related markers and said reference to identify said difference. 
     
     
         27 . The method of  claim 1 , wherein deconvolving said set of pregnancy-related markers comprises determining a relative contribution of a plurality of distinct fetal tissue types, and determining that said pregnant subject or said fetus of said pregnant subject is at said elevated risk of said pregnancy-related health condition based at least in part on said relative contribution of said plurality of distinct fetal tissue types. 
     
     
         28 . The method of  claim 27 , wherein said deconvolving comprises performing a constrained optimization. 
     
     
         29 . The method of  claim 1 , further comprising using a programmed computer to deconvolve sets of pregnancy-related markers identified in biological samples obtained from said pregnant subject at two or more different time points to determine sets of tissue-specific contributions of one or more tissue types among said sets of pregnancy-related markers, and comparing said sets of tissue-specific contributions to each other to determine that said pregnant subject or said fetus of said pregnant subject is at said elevated risk of said pregnancy-related health condition. 
     
     
         30 . A method for monitoring a pregnant subject or a fetus of said pregnant subject, comprising:
 (a) obtaining a biological sample from said pregnant subject;   (b) obtaining sequence information of nucleic acid molecules derived from said biological sample to identify a set of pregnancy-related markers in said biological sample; and   (c) using a programmed computer to deconvolve said set of pregnancy-related markers identified in (b) to determine tissue-specific contributions of one or more tissue types among said set of pregnancy-related markers, thereby monitoring a health of said pregnant subject or a health or developmental state of said fetus of said pregnant subject.