contemprary strategy for prenatal diagnosis

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contemprary strategy for prenatal diagnosis

  1. 1. Contemporary Strategy for Prenatal Diagnosis Professor Hassan Nasrat FRCS, FRCOG The Fetal Medicine Clinic The First Clinic JUCOG 2013 Sunday, July 28, 13
  2. 2. Maternal characteristics History Biophysical finding from US Findings from biochemical tests Current Objective Of Prenatal Care Is To Define Patient Specific Risk For Pregnancy Complications At Early Stage. Through Combining Data Data From: Sunday, July 28, 13
  3. 3. Diagnosisof aneuploidy Sunday, July 28, 13
  4. 4. “ Maternal Age Of 35 Should No Longer Be Used By Itself As A Cut-off To Determine Who Is Offered Screening Versus Who Is Offered Invasive Diagnostic Testing," “All Pregnant Women, Regardless Of Their Age, Should Have The Option Of Diagnostic Testing” 2007 Sunday, July 28, 13
  5. 5. Diagnosis  of   aneuploidy Screening  For   aneuploidy Sunday, July 28, 13
  6. 6. Diagnosis  of   aneuploidy Assessment  of  patient  specific  risk  for   aneuploidy Screening  For   aneuploidy Sunday, July 28, 13
  7. 7. Diagnosis  of   aneuploidy Non-­‐invasive  Methods Assessment  of  patient  specific  risk  for   aneuploidy Screening  For   aneuploidy Sunday, July 28, 13
  8. 8. Diagnosis  of   aneuploidy Non-­‐invasive  Methods Invasive  Methods Assessment  of  patient  specific  risk  for   aneuploidy Screening  For   aneuploidy Sunday, July 28, 13
  9. 9. Strategies  of  Screening  For   aneuploidy Sunday, July 28, 13
  10. 10. 0 25 50 75 100 95.00 90.00 87.00 82.00 91.00 81.00 75.00 87.00 69.00 75.00 21.001985- 1990 1991- 1995 1996- 2010 Maternal Serum AFP Genetic Ultrasound Maternal Serum Triple Marker Genetic Ultrasound First Trimester NT Maternal Serum QUAD marker Genetic Ultrasound First Trimester NT First Trimester NT and Serum Plus Selective NT,TR, and DV First Trimester NT and Serum First Trimester NT and Serum +Second-trimester QUAD History of Detection of Fetal Trisomy Sunday, July 28, 13
  11. 11. PRINCIPLES  OF  SCREENING Important  proper+es  of  a  screening  test  are  its  sensi+vity,   specificity,  and  predic+ve  values  nega+ve  and  posi+ve. Sunday, July 28, 13
  12. 12. PRINCIPLES  OF  SCREENING Important  proper+es  of  a  screening  test  are  its  sensi+vity,   specificity,  and  predic+ve  values  nega+ve  and  posi+ve. The  sensi(vity  and  specificity  cannot  be  used  to  es+mate   the  probability  of  the  disease  in  an  individual. Sunday, July 28, 13
  13. 13. PRINCIPLES  OF  SCREENING Important  proper+es  of  a  screening  test  are  its  sensi+vity,   specificity,  and  predic+ve  values  nega+ve  and  posi+ve. The  sensi(vity  and  specificity  cannot  be  used  to  es+mate   the  probability  of  the  disease  in  an  individual. Posi(ve   and   nega(ve   predic(ve   are   dependent   on   the   prevalence  of  the  disease Sunday, July 28, 13
  14. 14. PRINCIPLES  OF  SCREENING Important  proper+es  of  a  screening  test  are  its  sensi+vity,   specificity,  and  predic+ve  values  nega+ve  and  posi+ve. The  sensi(vity  and  specificity  cannot  be  used  to  es+mate   the  probability  of  the  disease  in  an  individual. Posi(ve   and   nega(ve   predic(ve   are   dependent   on   the   prevalence  of  the  disease The   likelihood   ra(o   are   independent   of   disease   prevalence  and  integrate  the  sensi+vity  and  specificity  of   screening  tests   Sunday, July 28, 13
  15. 15. The  likelihood  ra(o   Indicate by how much a given test result increases or decreases the probability of developinga condition. Sunday, July 28, 13
  16. 16. Every  woman  has  a  background  (priori)  risk  of  having   a  chromosomal  defective  baby.   Calculation  of  Patient  Specific  RISK   “Using  Positive  &  Negative  Likelihood  Ratio” Sunday, July 28, 13
  17. 17. Every  woman  has  a  background  (priori)  risk  of  having   a  chromosomal  defective  baby.   Calculation  of  Patient  Specific  RISK   “Using  Positive  &  Negative  Likelihood  Ratio” The  risk  may  increase  or  decrease  based  on  the  presence   (or  absence)  of  certain  marker  (s) Sunday, July 28, 13
  18. 18. Every  woman  has  a  background  (priori)  risk  of  having   a  chromosomal  defective  baby.   Calculation  of  Patient  Specific  RISK   “Using  Positive  &  Negative  Likelihood  Ratio” × The  risk  may  increase  or  decrease  based  on  the  presence   (or  absence)  of  certain  marker  (s) The  Background “Priori  Risk” Sunday, July 28, 13
  19. 19. Every  woman  has  a  background  (priori)  risk  of  having   a  chromosomal  defective  baby.   Calculation  of  Patient  Specific  RISK   “Using  Positive  &  Negative  Likelihood  Ratio” × The  Likelihood  ratio   as  Calculated  from  a   given  marker The  risk  may  increase  or  decrease  based  on  the  presence   (or  absence)  of  certain  marker  (s) The  Background “Priori  Risk” Sunday, July 28, 13
  20. 20. Every  woman  has  a  background  (priori)  risk  of  having   a  chromosomal  defective  baby.   Calculation  of  Patient  Specific  RISK   “Using  Positive  &  Negative  Likelihood  Ratio” × The  Likelihood  ratio   as  Calculated  from  a   given  marker a  new  priori   Posterior    Risk    For   the  next  test   The  risk  may  increase  or  decrease  based  on  the  presence   (or  absence)  of  certain  marker  (s) The  Background “Priori  Risk” Sunday, July 28, 13
  21. 21. Every  woman  has  a  background  (priori)  risk  of  having   a  chromosomal  defective  baby.   Calculation  of  Patient  Specific  RISK   “Using  Positive  &  Negative  Likelihood  Ratio” × The  Likelihood  ratio   as  Calculated  from  a   given  marker a  new  priori   Posterior    Risk    For   the  next  test   The  different   tests  are   independent The  risk  may  increase  or  decrease  based  on  the  presence   (or  absence)  of  certain  marker  (s) The  Background “Priori  Risk” Sunday, July 28, 13
  22. 22. 0.6 0.4 2.0 LR=1.7 LR=10.6 LR=2.0 AFP(MOM) UE3(MOM) hCG(MOM) Age Risk 30 years 1:900 Likelihood Ratio AFP UE3 hCG 1.7 × 10.4 × 2.0 × = Adjusted Risk 1:25 Normal DS Calculations  of  LRs  for  three  analytes.   At  a  MSAFP  level  of  0.6  MoM,  approximately  twice  as  many  fetuses  with   Down  syndrome  are  at  this  level  than  chromosomally  normal  fetuses.   Therefore,  the  LR  for  Down  syndrome  at  a  MSAFP  level  of  0.6  MoM  is  1.7. Sunday, July 28, 13
  23. 23. Every woman has a background or a priori risk that her fetus/baby has a chromosomal defect. A new individual “patient-specific” risk is calculated by multiplying the priori risk with a series of likelihood ratios obtained from screening tests. Summary Sunday, July 28, 13
  24. 24. Screening for Fetal Aneuploidy Sunday, July 28, 13
  25. 25. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Sunday, July 28, 13
  26. 26. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Biochemical Tests Sunday, July 28, 13
  27. 27. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Biochemical Tests Sonography Findings Sunday, July 28, 13
  28. 28. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Sonography Findings Sunday, July 28, 13
  29. 29. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Sunday, July 28, 13
  30. 30. Risk  of  Aneuploidy  based  on   Maternal  Age  and  Gestational   Week Sunday, July 28, 13
  31. 31. Sunday, July 28, 13
  32. 32. The   Risk   Is   Almost   Constant  At  Ages  15  To   25 Rises  Slowly  Between  25   To  35 Increases  Approximately   4-­‐fold  From  Ages  35  To   40  And   10-­‐fold  From  Ages  40  To   45;     Aneuploidy  and Maternal  Age   Sunday, July 28, 13
  33. 33. The   Risk   Is   Almost   Constant  At  Ages  15  To   25 Rises  Slowly  Between  25   To  35 Increases  Approximately   4-­‐fold  From  Ages  35  To   40  And   10-­‐fold  From  Ages  40  To   45;     Aneuploidy  and Maternal  Age   Sunday, July 28, 13
  34. 34. The   Risk   Is   Almost   Constant  At  Ages  15  To   25 Rises  Slowly  Between  25   To  35 Increases  Approximately   4-­‐fold  From  Ages  35  To   40  And   10-­‐fold  From  Ages  40  To   45;     Aneuploidy  and Maternal  Age   Sunday, July 28, 13
  35. 35. Risk  of  Aneuploidy  based  on   Previous  Trisomy Sunday, July 28, 13
  36. 36. Previous Trisomy 21 increases the risk of recurrence by a factor of 0.75% above the maternal and gestational age-related risk for trisomy 21 at the time of testing. A  previous  trisomy  21: ✦For  35  years  old  woman  the  risk  at  12  weeks  of  gestation   increases  from  1  in  249  (0.40%)  to  1  in  87  (1.15%). ✦For  25  years  old  woman  the  risk  increases  from  1  in  946   (0.106%)  to  1  in  117  (0.856%). Sunday, July 28, 13
  37. 37. The risk for trisomies increases with maternal age. The risk of Turner syndrome and triploidy does not change with maternal age. The earlier the gestation, the higher the risk for chromosomal defects.  A previous fetus or baby with a trisomy increases the risk in a current pregnancy by 0.75% over a priori risk. Summary Sunday, July 28, 13
  38. 38. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Sunday, July 28, 13
  39. 39. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Biochemical Tests Sunday, July 28, 13
  40. 40. In order to take account of sources of variation, the concentration of each marker is expressed as a multiple of the median for pregnancies of the same gestational age (MoM). Sunday, July 28, 13
  41. 41. cted uE3 (MoM) UnaffectedDown’s syndrome Down’s syndromeUnaffectedfected Down’s syndrome Unaffected AFP (MoM) uE3 (MoM) UnaffectedDown’s syndrome Nuchal translucency (MoM) Down’s syndromeUnaffectedDown’s syndrome PAPP-A (MoM) Unaffected Down’s syndrome Unaffected AFP (MoM) uE3 (MoM) UnaffectedDown’s syndrome Nuchal translucency (MoM) Down’s syndromeUnaffectedDown’s syndrome PAPP-A (MoM) Unaffected Nuchal tra Unaffected Unaffected Inhibin-A (MoM) Down’s syndrome PAPP-A (MoM) Unaffected Unaffected Down’s syndrome free ß 9 Down's syndrome Unaffected Inhibin-A (MoM) Unaffected Down’s syndrome free ß-hCG (MoM) Down’s syndrome Unaffected AFP (MoM) uE3 (MoM) UnaffectedDown’s syndrome Nuchal translucency (MoM) Down’s syndromeUnaffected Down's syndrome Unaffected Down’s syndrome PAPP-A (MoM) Unaffected Unaffected Down’s syndrome UnaffectedD Syndrome UnaffectedD Syndrome D SyndromeUnaffected Unaffected Unaffected Unaffected D Syndrome D Syndrome D Syndrome Sunday, July 28, 13
  42. 42. ✦Maternal Weight: ✦Ethnic Group: ✦In Vitro Fertilization (IVF): ✦Insulin Dependent Diabetes Mellitus (IDDM): ✦Smoking: ✦Previous affected pregnancies ✦Vaginal bleeding ✦Results of screening in a previous pregnancy FACTORS AFFECTING THE TEST Sunday, July 28, 13
  43. 43. THREE SCREENING OPTIONS 2nd Trimester Quad 1st Trimester Combined Test 1st and 2nd Trimester Fully Integrated Test Serum Integrated Stepwise Sequential Contingent Sequential Screen Sunday, July 28, 13
  44. 44. THREE SCREENING OPTIONS 1st Trimester Combined Test Sunday, July 28, 13
  45. 45. 1...9 10 11 12 13 14 15 16 17 18 19 20......40 10 to 14 wks Blood Draw COMBINED INTEGRATED 11 to 14 wks Nuchal Translucency PAPPA-A hCG +Measurement of CRL Sunday, July 28, 13
  46. 46. COMBINED TEST 1 Blood Drawn: 10 Weeks 0 days to 13 weeks 6 days Test: PAPPA-A and hCG 2 ULTRASOUND: 11 Weeks 2 days to 14 weeks 2 days Test: Measure Nuchal Translucency First Trimester Cut off (mid- trimester risk) False Positive Rate Detection Rate 1:80 2.02% 72.57% 1:100 2.54% 74..99% 1:120 3.03% 76.89% Risk Assessment •Trisomy 21 •Trisomy 18 Sunday, July 28, 13
  47. 47. 0 10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 Combined Test Overall Detection Rate 85% MATERNAL AGE DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE 85% 50% Sunday, July 28, 13
  48. 48. THREE SCREENING OPTIONS 2nd Trimester Quad 1st Trimester Combined Test Sunday, July 28, 13
  49. 49. 1...9 10 11 12 13 14 15 16 17 18 19 20......40 15 to 20wks Blood Draw Quad Test Quad AFP hCG Ue3 Inhibin Sunday, July 28, 13
  50. 50. QUAD TEST 0 25 50 75 100 80.00 67.00 97.00 80.00 85.00 60.00 Tri 21 Tri 18 Anecephaly Spina Bifida Abd W D SLOS Detection Rate Sunday, July 28, 13
  51. 51. What Does A Negative Test Miss? 0 10 20 30 40 20 33 3 20 15 40 Tri 21 Tri 18 Anecephaly Spina Bifida Abd W D SLOS Percent of Birth Defects Not Detected Sunday, July 28, 13
  52. 52. THREE SCREENING OPTIONS 2nd Trimester Quad 1st Trimester Combined Test 1st and 2nd Trimester Fully Integrated Test Serum Integrated Sequential Screen Contingent Screen Sunday, July 28, 13
  53. 53. 1...9 10 11 12 13 14 15 16 17 18 19 20......40 10 to 14 wks Fully Integrated Measurement of CRL + PAPPA-A hCG 11 to 14 wks Nuchal Translucency Sunday, July 28, 13
  54. 54. 1...9 10 11 12 13 14 15 16 17 18 19 20......40 10 to 14 wks Results are Reported after The Second Blood Test 15 to 20 wks Fully Integrated AFP hCG Ue3 InhibinMeasurement of CRL + PAPPA-A hCG 11 to 14 wks Nuchal Translucency Sunday, July 28, 13
  55. 55. 1...9 10 11 12 13 14 15 16 17 18 19 20......40 10 to 14 wks Serum Integrated Measurement of CRL + PAPPA-A hCG Sunday, July 28, 13
  56. 56. 1...9 10 11 12 13 14 15 16 17 18 19 20......40 10 to 14 wks Results are Reported after The Second Blood Test 15 to 20 wks Serum Integrated AFP hCG Ue3 InhibinMeasurement of CRL + PAPPA-A hCG Sunday, July 28, 13
  57. 57. First-trimester Screening Screen Positive CVS Final Result incorporate 1st and 2nd results Screen Negative QUAD Sequential Screen Sunday, July 28, 13
  58. 58. First-trimester Screening Very High Risk >1 in 50 CVS Contingent Screen Intemediate Risk (1in 50 to 1 in 1000 QUAD Low Risk <1 in 2000 NoAdditional Test Sunday, July 28, 13
  59. 59. First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  60. 60. 0 25 50 75 100 First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  61. 61. 0 25 50 75 100 75 First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  62. 62. 0 25 50 75 100 75 85 NT NT + PAPP-A & β-hCG First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  63. 63. 0 25 50 75 100 75 85 75 NT AFP + Ue3 & β-hCG NT + PAPP-A & β-hCG First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  64. 64. 0 25 50 75 100 75 85 75 NT AFP + Ue3 & β-hCG NT + PAPP-A & β-hCG First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  65. 65. 0 25 50 75 100 75 85 75 NT AFP + Ue3 & β-hCG NT + PAPP-A & β-hCG 85 AFP + Ue3 & β-hCG & Inhibin “QUAD“ First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  66. 66. 0 25 50 75 100 75 85 NT NT + PAPP-A & β-hCG 85 AFP + Ue3 & β-hCG & Inhibin “QUAD“ First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  67. 67. 0 25 50 75 100 75 85 NT NT + PAPP-A & β-hCG 85 AFP + Ue3 & β-hCG & Inhibin “QUAD“ 95 NT + PAPP-A & β-hCG “QUAD” First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  68. 68. 0 25 50 75 100 75 85 NT NT + PAPP-A & β-hCG 85 AFP + Ue3 & β-hCG & Inhibin “QUAD“ 95 NT + PAPP-A & β-hCG “QUAD” What  if  NT   is  Not  Available? First Trimester Second Trimester 1st & 2nd Trimester Sunday, July 28, 13
  69. 69. 0 25 50 75 100 75 85 NT NT + PAPP-A & β-hCG 85 AFP + Ue3 & β-hCG & Inhibin “QUAD“ 95 85 NT + PAPP-A & β-hCG “QUAD” PAPP-A & β-hCGWhat  if  NT   is  Not  Available? First Trimester Second Trimester 1st & 2nd Trimester “QUAD” Sunday, July 28, 13
  70. 70. 0 10 20 30 40 50 60 70 80 90 100 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 Fully Integrated Overall Detection Rate 95% MATERNAL AGE DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE 90% 50% Sunday, July 28, 13
  71. 71. 0 25 50 75 100 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 Serum Integrated Overall Detection Rate 85% MATERNAL AGE DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE 80% 72% Sunday, July 28, 13
  72. 72. 0 10 20 30 40 50 60 70 80 90 100 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 Fully Integrated Overall Detection Rate 95% MATERNAL AGE DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE 90% 50% Sunday, July 28, 13
  73. 73. 0 10 20 30 40 50 60 70 80 90 100 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 Fully Integrated Overall Detection Rate 95% MATERNAL AGE DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE 90% 50% Sunday, July 28, 13
  74. 74. 0 10 20 30 40 50 60 70 80 90 100 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 45 Fully Integrated Overall Detection Rate 95% MATERNAL AGE DETECTION RATE OF TRISOMY 21 BASED ON MATERNAL AGE 90% 50% HOW? 90+% Sunday, July 28, 13
  75. 75. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Biochemical Tests Sunday, July 28, 13
  76. 76. Screening for Fetal Aneuploidy Maternal Age Previous History Tests Biochemical Tests Sonography Findings Sunday, July 28, 13
  77. 77. FIRST TRIMESTER SECOND TRIMESTER Sunday, July 28, 13
  78. 78. 1ST TRIMESTER SCREENING Sunday, July 28, 13
  79. 79. Nasal Bone Tricuspid Regurgitation Ductus Venousus Figure 3 Four-chamber view illustrating an endocardial cushion defect in which a ventricular (VSD) and atrial (ASD) septal defect are present. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. SUGGESTED USE OF FETAL ECHOCARDIOGRAPHY AS PART OF THE GENETIC SONOGRAM GIVEN CURRENT SCREENING TECHNOLOGIES At present, common screening tests for trisomy 21 may include any of the following: (1) first-trimester combined NT and serum screening, (2) first-trimester combined NT and serum screening plus second-trimester QUAD screening, (3) first-trimester serum and second-trimester Genetic sonography as an adjunct to first-trimester NT and serum and/or second-trimester serum screening When genetic sonography was first introduced in the early 1990s it was an option for screening for trisomy 21 in women less than 35 years of age for two reasons: (1) the detection rate was similar to or higher than that using MSAFP screening, and (2) the ultrasound exam only required measurements of the biparietal diameter, femur length and nuchal skin fold (Table 1). However, as more analytes were added, second-trimester maternal serum (triple and QUAD) screening increased the detection rate for trisomy 21, was easier to use, and did not require the specialized ultrasound skills needed to keep the genetic sonogram comparable in terms of detection rates (Table 2). Investigators have reported the use of genetic sono- graphy as an adjunct to other screening protocols. In 2001, Roberto Romero and I11 reported offer- ing genetic sonography to women considered to be at moderate risk (1 : 190–1 : 1000) for trisomy 21 Figure 4 Four-chamber view illustrating a ventricular septal defect (VSD) at the level of the inflow tracts. (a) B-mode image; (b) power Doppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle. Sunday, July 28, 13
  80. 80. Nasal Bone Sunday, July 28, 13
  81. 81. note THREE distinct lines: Sunday, July 28, 13
  82. 82. note THREE distinct lines: Sunday, July 28, 13
  83. 83. The Nasal Bone Is Absent In: 0 18 35 53 70 65.00 50.00 30.00 2.00 Tri 21 Tri 18 Tri 13 Normal Sunday, July 28, 13
  84. 84. 0 15.00 30.00 45.00 60.00 18.00 19.00 52.00 52.00 45-54 55-64 65-74 75-84 Absent Nasal Bone and CRL Likelihood Ratio for DS Cicero S et al US Ob&Gyn, 2004, 23 Sunday, July 28, 13
  85. 85. In  chromosomal  normal  fetuses  the   incidence   of  absent  nasal  bone   is  less   than  1%  in  Caucasian  populations  and   about  10%  in  Afro-­‐Caribbean. 31.00 9.00 14.00 15.00 Caucasian Asian Ethnicity of Mother Cicero et al US OB and Gyn 2004 Liklihood Ratios For Down Syndrome - Absent Nasal Bone Sunday, July 28, 13
  86. 86. For   a   false   positive   rate   of   5%,   screening   by   a   combination   of   sonography   for   fetal   NT   and   nasal   bone  and  maternal  serum  free  b-­‐hCG   and   PAPP-­‐A   can   potentially   identify   more   than   95%   of   trisomy   21   pregnancies. The  Nasal  Bone Sunday, July 28, 13
  87. 87. DV Blood Flow Sunday, July 28, 13
  88. 88. In   more   than   5,000   pregnancies,   including     280   fetuses  with  trisomy  21: 0 20 40 60 80 DV Nomral 5 80 Abnormal  DV  flow  in  about  80%  of  trisomy  21  fetuses   and  in  about  5%  of  chromosomally  normal  fetuses                                                                                            (Nicolaides  2004)   Sunday, July 28, 13
  89. 89. Sunday, July 28, 13
  90. 90. Tricuspid Rugurge Sunday, July 28, 13
  91. 91. Tricuspid regurgitation in screening for trisomies Tricuspid regurgitation in screening for trisomies 21, 18 and 13 and Turner syndrome at 11 + 0 to 13 + 6 weeks of gestation K. O. KAGAN*†, C. VALENCIA*, P. LIVANOS*, D. WRIGHT‡ and K. H. NICOLAIDES Ultrasound Obstet Gynecol 2009; 33: 18–22, 2008 Sunday, July 28, 13
  92. 92. 0 15 30 45 60 0.9 55.7 33.3 30 37 Normal Tr1 21 Tri 18 Tri 13 Turner Percentage of Tricuspid regurgitation among normal and abnormal Sunday, July 28, 13
  93. 93. 0 10 20 30 40 50 60 70 80 90 100 91 100 100 100 T21 T18 Tris 13 Turner S Detection rates at 3% FPR using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with and without assessment of tricuspid blood flow Total 96% + 6% Sunday, July 28, 13
  94. 94. Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  95. 95. 0 10 20 30 40 50 60 70 80 90 100 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  96. 96. 0 10 20 30 40 50 60 70 80 90 100 80.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  97. 97. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  98. 98. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  99. 99. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  100. 100. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 94.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  101. 101. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 94.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  102. 102. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 94.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  103. 103. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 94.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  104. 104. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 94.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  105. 105. 0 10 20 30 40 50 60 70 80 90 100 80.00 86.00 91.00 93.00 94.00 FPR 1.0 FPR 2.0 FPR 3.0 FPR 4.0 FPR 5.0 Detection rates at given FPR levels using screening by maternal age, fetal NT, FHR, free β-hCG and PAPP-A with andwithoutassessmentoftricuspidbloodflow. Total 92% + 12% Total 95% Total 96% Total 96% Total 96% + 11% + 5% + 3% + 2% Sunday, July 28, 13
  106. 106. Nasal Bone Tricuspid Regurgitation Ductus Venousus Figure 3 Four-chamber view illustrating an endocardial cushion defect in which a ventricular (VSD) and atrial (ASD) septal defect are present. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. SUGGESTED USE OF FETAL ECHOCARDIOGRAPHY AS PART OF THE GENETIC SONOGRAM GIVEN CURRENT SCREENING TECHNOLOGIES At present, common screening tests for trisomy 21 may include any of the following: (1) first-trimester combined NT and serum screening, (2) first-trimester combined NT and serum screening plus second-trimester QUAD screening, (3) first-trimester serum and second-trimester Genetic sonography as an adjunct to first-trimester NT and serum and/or second-trimester serum screening When genetic sonography was first introduced in the early 1990s it was an option for screening for trisomy 21 in women less than 35 years of age for two reasons: (1) the detection rate was similar to or higher than that using MSAFP screening, and (2) the ultrasound exam only required measurements of the biparietal diameter, femur length and nuchal skin fold (Table 1). However, as more analytes were added, second-trimester maternal serum (triple and QUAD) screening increased the detection rate for trisomy 21, was easier to use, and did not require the specialized ultrasound skills needed to keep the genetic sonogram comparable in terms of detection rates (Table 2). Investigators have reported the use of genetic sono- graphy as an adjunct to other screening protocols. In 2001, Roberto Romero and I11 reported offer- ing genetic sonography to women considered to be at moderate risk (1 : 190–1 : 1000) for trisomy 21 Figure 4 Four-chamber view illustrating a ventricular septal defect (VSD) at the level of the inflow tracts. (a) B-mode image; (b) power Doppler image confirming flow at the level of the VSD. LV, left ventricle; RV, right ventricle. Value of Adding Multiple Markers Sunday, July 28, 13
  107. 107. Benefit of Multiple Ultrasound Markers NT + Serum NT+Serum + Nasal Bone + Heart + DV Tri 21 Tri 81 1st Trimester 75% 96% 69% 90% NT + Serum NT+Serum + NasalBone + Heart + DV Sunday, July 28, 13
  108. 108. 2ND TRIMESTER SCREENING “Genetic Sonography” Sunday, July 28, 13
  109. 109. Is based on the application of the likelihood ratios obtained from multiple independent ultrasound markers markers in adjusting a priori risk to determine a patient’s specific risk of carrying a fetus with DS Genetic  Ultrasound   Sunday, July 28, 13
  110. 110. Likelihood ratios (LR): for each marker are calculated by dividing the sensitivity of a particular marker by its false- positive rate. LR < 1 LR > 1-5 LR > 5-10 LR > 10 Small increase Moderate increase Large Increase Decrease Probability Sunday, July 28, 13
  111. 111. The relative risk “RR”: is the probability of a fetus having trisomy 21 when compared with a fetus without this condition. e.g. The presence of an ultrasound marker with a RR of 4 suggests a four-fold increasefromthepreviousrisk. Sunday, July 28, 13
  112. 112. Example: A pericardial effusion with a relative risk 10.02. APatientWith Prior Risk ForTrisomy 21 Is 1 In 270 Sunday, July 28, 13
  113. 113. Calculation of Risk: 1. Divide 1/(270–1) = 0.0037 2. Multiply the prior risk (0.0037) by (10.02) Calculation = 0.0037 × 10.02 = 0.037 3. Divide 1/0.037 = 28 Example: A pericardial effusion with a relative risk 10.02. APatientWith Prior Risk ForTrisomy 21 Is 1 In 270 The New Risk For Trisomy 21 is 1 in 28 Sunday, July 28, 13
  114. 114. Example: Normal ultrasound examination study in which none of the ultrasound markers is present Patient with Prior risk for trisomy 21 is 1 in 100 The RR following a normal study is 0.11 Sunday, July 28, 13
  115. 115. Calculation of Risk: 1.Divide 1/(100–1) = 0.01 2.Multiply the prior risk (0.01) by the RR for both findings, 0.11 3.Calculation = 0.01 × 0.11 = 0.0011 4.Divide 1/00.11 = 900 Example: Normal ultrasound examination study in which none of the ultrasound markers is present Patient with Prior risk for trisomy 21 is 1 in 100 The RR following a normal study is 0.11 The New Risk For Trisomy 21 is 1 in 900 Sunday, July 28, 13
  116. 116. Head Heart Abdomen Sunday, July 28, 13
  117. 117. Head Heart Abdomen ➡CP ➡CNS  (other  than  CP) ➡NSF Sunday, July 28, 13
  118. 118. Head Heart Abdomen ➡CP ➡CNS  (other  than  CP) ➡NSF ➡VSD ➡Rt  to  Lt.  Disp ➡Outflow  tract   abnormalities* ➡Pericardial  Effusion ➡Tricuspid  or  mitral   regurgitation Sunday, July 28, 13
  119. 119. Head Heart Abdomen ➡CP ➡CNS  (other  than  CP) ➡NSF ➡VSD ➡Rt  to  Lt.  Disp ➡Outflow  tract   abnormalities* ➡Pericardial  Effusion ➡Tricuspid  or  mitral   regurgitation ➡Hyperechoic  Bowel ➡Pyelectasis   Sunday, July 28, 13
  120. 120. CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  121. 121. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  122. 122. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis 88.26 12.54 Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  123. 123. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis 88.26 12.54 5.89 10.02 Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  124. 124. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis 88.26 12.54 5.89 10.02 4.57 5.65 Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  125. 125. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis 88.26 12.54 5.89 10.02 4.57 5.65 Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  126. 126. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis 88.26 12.54 5.89 10.02 4.57 5.65 Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  127. 127. 0 20.00 40.00 60.00 80.00 71.31 24.85 CNS abnormalities IncreasedNFS VSD R-LDisproportion PericaridalEffusion TricuspidRegurg HyperechoicBowel Pyelectasis 88.26 12.54 5.89 10.02 4.57 5.65 Head Structural heartdefects Functional heartdefects Abdomen (RR) for CV and non- CV ultrasound markers in 80 second-trimester fetuses with trisomy 215 (with sensitivity 91% and false-positive rate 14%) DeVore GR. 2000 Sunday, July 28, 13
  128. 128. 0 25 50 75 100 60 91 Without Color Doppler With Color Doppler The use of fetal echocardiography when performing the genetic sonogram: 98% detection rate for trisomy 21 in high-risk women Devore, 2006 Sunday, July 28, 13
  129. 129. Meta-analysis of second-trimester markers for trisomy 21 Harris Birthright Research Centre for Fetal Medicine, King’s College Hospital, London, UK (2012) The aim: to examine the screening p e r f o r m a n c e o f s e c o n d - t r i m e s t e r sonographic markers for the detection of trisomy 21. Sunday, July 28, 13
  130. 130. 0.460.710.740.800.920.900.800.940.80 23.26 21.48 4.80 3.72 7.77 10.82 19.18 25.78 5.80 ICF Ventriculomegaly IncreasedNF HyperechogenicB. Mildhydronephrosis ShortFemur ShortHumerus ARSA AbsentNasalBone Sunday, July 28, 13
  131. 131. 0.460.710.740.800.920.900.800.940.80 23.26 21.48 4.80 3.72 7.77 10.82 19.18 25.78 5.80 ICF Ventriculomegaly IncreasedNF HyperechogenicB. Mildhydronephrosis ShortFemur ShortHumerus ARSA AbsentNasalBone ✤Ventriculomegaly, NF And ARSA Increases The Risk By 3-4 Fold ✤Hypoplastic Nasal Bone Increases The Risk By 6-7 Fold Sunday, July 28, 13
  132. 132. ✤In The Absence Of All Major Defects And Markers There Is A7.7-fold Reduction In Risk For Trisomy 21. ✤The Detection Of Any One Of The Markers Should Stimulate The Sonographer To Look For All Other Markers Or Defects. ✤The Post- Test Odds For Trisomy 21 Is Derived By Multiplying The Pre-test Odds With The Positive LR For Each Detected Marker And The Negative LR For Each Marker Demonstrated To BeAbsent. ✤In The Case Of Most Isolated Markers, Including Intracardiac Echogenic Focus, Echogenic Bowel, Mild Hydronephrosis And Short Femur, There Is Only A Small Effect On Modifying The Pre-test Odds. Sunday, July 28, 13
  133. 133. 0 0.25 0.50 0.75 1.00 LR 0.37 LR 0.10 The LR for trisomy 21 in the absence of sonographic markers LR 0.37 RR 0.11 Nicoloides et al Devore Sunday, July 28, 13
  134. 134. Genetic sonography as an adjunct to first-trimester NT and serum and/or second-trimester serum screening 0 25.00 50.00 75.00 100.00 90.00 98.00 90.00 81.00 93.00 81.00 CombinedTest 1st &2nd Trim Integrated QUAD Aagaard-Tillery KM, et al First and SecondTrimester Evaluation of Risk Research Consortium. Role of second- trimestergeneticsonographyafterDownsyndromescreening.ObstetGynecol2009;114 Sunday, July 28, 13
  135. 135. NT plus Serum NT, Serum, NB,TR, DV, Heart 83% 96% 1st Trimester Options 1st Trimester Options Sunday, July 28, 13
  136. 136. Serum Integrated Fully Integrated 80% 85% 2nd Trimester Detection Rate 2nd Trimester Options QUAD 90% QUAD + Genetic U/S 2nd Trimester Detection Rate 99% 2nd + 1st Trimester Options Sunday, July 28, 13
  137. 137. Putting It Together Sunday, July 28, 13
  138. 138. Initial Testing Maternal Age Serum Screening Nuchal Translucency + + Sunday, July 28, 13
  139. 139. > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 Sunday, July 28, 13
  140. 140. High-Risk (>1 in 100) (2% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 Sunday, July 28, 13
  141. 141. High-Risk (>1 in 100) (2% of Polulation) CVS > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 Sunday, July 28, 13
  142. 142. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 Sunday, July 28, 13
  143. 143. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 Sunday, July 28, 13
  144. 144. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing Intermediate-Risk (1 in 101 to 1 in 1,000) (16% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 Sunday, July 28, 13
  145. 145. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing Intermediate-Risk (1 in 101 to 1 in 1,000) (16% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 UltrasoundExaminationfor •AbsentNasalBone •AbnormalDuctusVenosusFlow •TricuscupidRrgurgitation Sunday, July 28, 13
  146. 146. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing Intermediate-Risk (1 in 101 to 1 in 1,000) (16% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 UltrasoundExaminationfor •AbsentNasalBone •AbnormalDuctusVenosusFlow •TricuscupidRrgurgitation Positive Sunday, July 28, 13
  147. 147. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing Intermediate-Risk (1 in 101 to 1 in 1,000) (16% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 UltrasoundExaminationfor •AbsentNasalBone •AbnormalDuctusVenosusFlow •TricuscupidRrgurgitation Positive Negative Sunday, July 28, 13
  148. 148. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing Intermediate-Risk (1 in 101 to 1 in 1,000) (16% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 UltrasoundExaminationfor •AbsentNasalBone •AbnormalDuctusVenosusFlow •TricuscupidRrgurgitation Positive Negative If This is Not Available Sunday, July 28, 13
  149. 149. High-Risk (>1 in 100) (2% of Polulation) CVS Low-Risk (>1in1001in10,100) (82%ofPolulation) No Further Testing Intermediate-Risk (1 in 101 to 1 in 1,000) (16% of Polulation) > 90% Detection Rate False Positive Rate 2% Estimated Risk For Trisomy 21 UltrasoundExaminationfor •AbsentNasalBone •AbnormalDuctusVenosusFlow •TricuscupidRrgurgitation Positive Negative If This is Not Available Genetic Sonography Sunday, July 28, 13
  150. 150. Examination of fetal cells from maternal peripheral blood: Cell-free fetal DNA in maternal plasma:   Non-­‐invasive   diagnosis Sunday, July 28, 13
  151. 151. Examination of fetal cells from maternal peripheral blood: Cell-free fetal DNA in maternal plasma “cffDNA”:   Non-­‐invasive   diagnosis Sunday, July 28, 13
  152. 152. NIPT Non Invasive Prenatal Testing Screening or Diagnosis Sunday, July 28, 13
  153. 153. It is now established that trisomy 21 can be detected reliably from 10 weeks’ gestation in high-risk singleton pregnancies with superior sensitivity (> 99%) and specificity (false-positive rate < 1%) compared with conventional screening methods. Trisomy 18 and 13 are also detectable, but test accuracy is less consistent than that for trisomy 21. Sunday, July 28, 13
  154. 154. Clinical validity: Theclinicalutility: Sunday, July 28, 13
  155. 155. The ability of a test to predict the risk of an outcome and to categorize patients with different outcomes into separate risk classes. Clinical validity: Theclinicalutility: Sunday, July 28, 13
  156. 156. The ability of a test to predict the risk of an outcome and to categorize patients with different outcomes into separate risk classes. Clinical validity: Theclinicalutility: The ability of a test to improve health outcomes for patients. Specifically, the test results must change clinical decision- making,andthesechangesshouldbebeneficialtopatients. Sunday, July 28, 13
  157. 157. The ability of a test to predict the risk of an outcome and to categorize patients with different outcomes into separate risk classes. Clinical validity: Theclinicalutility: The ability of a test to improve health outcomes for patients. Specifically, the test results must change clinical decision- making,andthesechangesshouldbebeneficialtopatients. There are currently no studies on the impact of DNA- based NIPTon patient management or outcome. Sunday, July 28, 13
  158. 158. Current Screening and/or ultrasound High risk for aneuploidy Pretest counseling Invasive diagnosis Genetic Counseling TOP •Continue Pregnancy •Prepare for affected infant •Deliver at hospital with special newborn services Serum screening and/or ultrasound examination Invasive cytogenetic diagnosis Trisomy 21 Genetic counseling TOP •Continue pregnancy •Prepare for affectedt infavnct •Deliver at hospital with special newborn servcie Treat Fetus Sequencing of Cell Free DNA Current Future And/Or Sunday, July 28, 13
  159. 159. From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges Diana W Bianchi Nature Medicine 18, 1041–1051 (2012) doi:10.1038/nm.2829 Published online 06 July 2012 Thus far, the focus of personalized medicine has been the prevention and treatment of conditions that affect adults. Although advances in genetic technology have been applied more frequently to prenatal diagnosis than to fetal treatment, genetic and genomic information is beginning to influence pregnancy management. Recent developments in sequencing the fetal genome combined with progress in understanding fetal physiology using gene expression arrays indicate that we could have the technical capabilities to apply an individualized medicine approach to the fetus. Here I review recent advances in prenatal genetic diagnostics, the challenges associated with these new technologies and how the information derived from them can be used to advance fetal care. Historically, the goal of prenatal diagnosis has been to provide an informed choice to prospective parents. We are now at a point where that goal can and should be expanded to incorporate genetic, genomic and transcriptomic data to develop new approaches to fetal treatment. Sunday, July 28, 13
  160. 160. Sunday, July 28, 13
  161. 161. Thanks Sunday, July 28, 13

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