1 00:00:02,530 --> 00:00:03,363 [Instructor] In this lecture, 2 00:00:03,363 --> 00:00:05,730 we're going to talk about genetic testing 3 00:00:05,730 --> 00:00:08,340 and look at it across the lifespan, 4 00:00:08,340 --> 00:00:12,720 everything from preconception, prenatal, newborn, 5 00:00:12,720 --> 00:00:15,210 pediatric, adult geriatric. 6 00:00:15,210 --> 00:00:20,130 And take a look at how the testing might differ 7 00:00:20,130 --> 00:00:21,990 at each stage of life, 8 00:00:21,990 --> 00:00:24,990 the implications at each stage 9 00:00:24,990 --> 00:00:29,700 and how that might influence the a patient's decision 10 00:00:29,700 --> 00:00:31,800 and their healthcare provider's decisions 11 00:00:31,800 --> 00:00:35,073 to pursue certain genetic testing or not. 12 00:00:36,570 --> 00:00:39,360 So just starting here at the beginning, as I mentioned, 13 00:00:39,360 --> 00:00:41,910 we're going to go through really all the stages of life 14 00:00:41,910 --> 00:00:44,190 and look at genetic testing there 15 00:00:44,190 --> 00:00:47,340 and how the impact can really be quite different 16 00:00:47,340 --> 00:00:50,220 from ethical, legal, and social perspectives, 17 00:00:50,220 --> 00:00:52,500 tying in what we learned last week here. 18 00:00:52,500 --> 00:00:54,060 And so in continuing that discussion 19 00:00:54,060 --> 00:00:57,690 and continuing those thoughts, more specifically 20 00:00:57,690 --> 00:01:00,420 in thinking about how genetic testing is done 21 00:01:00,420 --> 00:01:01,920 at each of those stages of life 22 00:01:01,920 --> 00:01:05,310 and how it might differ depending upon the stage of life 23 00:01:05,310 --> 00:01:07,923 where a person is considering genetic testing. 24 00:01:08,820 --> 00:01:09,990 When we're talking about prenatal 25 00:01:09,990 --> 00:01:11,850 or preconception genetic testing, 26 00:01:11,850 --> 00:01:14,940 it's typically recommended for specific diseases 27 00:01:14,940 --> 00:01:17,310 known to exist in the mother or father's family history. 28 00:01:17,310 --> 00:01:19,860 So this is where we'd be thinking, well, 29 00:01:19,860 --> 00:01:23,430 you might be a carrier for certain rare genetic diseases. 30 00:01:23,430 --> 00:01:26,460 For example, if there is a history of it 31 00:01:26,460 --> 00:01:30,910 in one or both of the individual's 32 00:01:32,280 --> 00:01:34,410 family histories in the couple 33 00:01:34,410 --> 00:01:37,650 that's considering having a child. 34 00:01:37,650 --> 00:01:40,350 And this is also true not just with 35 00:01:40,350 --> 00:01:42,900 if you have a specific family history of conditions, 36 00:01:42,900 --> 00:01:47,490 but also this gets back to the ethnicity 37 00:01:47,490 --> 00:01:51,090 or racial group to which the individual belongs. 38 00:01:51,090 --> 00:01:54,240 Certainly can have an impact on the likelihood 39 00:01:54,240 --> 00:01:56,490 that they would be carriers for certain conditions. 40 00:01:56,490 --> 00:01:59,280 And there are certain genetic testing panels 41 00:01:59,280 --> 00:02:02,340 that can be ordered that are specifically designed 42 00:02:02,340 --> 00:02:04,890 to test for genetic diseases 43 00:02:04,890 --> 00:02:09,603 that are most common in certain ethnicities or races. 44 00:02:10,950 --> 00:02:13,290 Neonatal screening is mandated by the state 45 00:02:13,290 --> 00:02:15,401 and includes tests for genetic diseases. 46 00:02:15,401 --> 00:02:19,950 These are not genetic tests necessarily. 47 00:02:19,950 --> 00:02:22,830 They're typically biochemical tests that are performed 48 00:02:22,830 --> 00:02:26,610 on the blood sample that's taken shortly after birth, 49 00:02:26,610 --> 00:02:28,500 the heel prick test. 50 00:02:28,500 --> 00:02:31,530 But they often are testing for genetic diseases, 51 00:02:31,530 --> 00:02:32,940 but they're just more so looking 52 00:02:32,940 --> 00:02:34,830 for the biochemistry that you would be able 53 00:02:34,830 --> 00:02:36,780 to assess in the blood, 54 00:02:36,780 --> 00:02:39,900 and that would be indicative of a high likelihood 55 00:02:39,900 --> 00:02:43,290 that an individual has a particular genetic condition. 56 00:02:43,290 --> 00:02:45,120 So, as we'll talk about shortly, 57 00:02:45,120 --> 00:02:47,880 that would always be followed up with a reflex test, 58 00:02:47,880 --> 00:02:48,750 what's called a reflex test. 59 00:02:48,750 --> 00:02:52,290 So if it comes back positive in a screen, 60 00:02:52,290 --> 00:02:54,870 it would immediately go, for a biochemical test, 61 00:02:54,870 --> 00:02:56,520 it would immediately go for a more 62 00:02:56,520 --> 00:02:59,010 of a specific genetic test. 63 00:02:59,010 --> 00:03:00,810 Pediatric genetic testing occurs 64 00:03:00,810 --> 00:03:03,330 in children demonstrating possible symptoms 65 00:03:03,330 --> 00:03:05,970 of a genetic disease like intellectual disability, 66 00:03:05,970 --> 00:03:07,920 which is commonly associated 67 00:03:07,920 --> 00:03:11,170 with a genetic abnormality as we've been talking about 68 00:03:12,030 --> 00:03:13,770 earlier in the semester. 69 00:03:13,770 --> 00:03:17,340 And this pediatric genetics, you know, 70 00:03:17,340 --> 00:03:19,980 there are some really specific considerations here 71 00:03:19,980 --> 00:03:22,530 because as you can appreciate, 72 00:03:22,530 --> 00:03:26,940 you want to maintain autonomy 73 00:03:26,940 --> 00:03:29,820 and decision making for a genetic test result 74 00:03:29,820 --> 00:03:33,600 for an individual and in the pediatric setting, 75 00:03:33,600 --> 00:03:35,340 if it's, you know, for a child 76 00:03:35,340 --> 00:03:38,790 and the child doesn't have the ability 77 00:03:38,790 --> 00:03:41,580 to make that an an informed decision 78 00:03:41,580 --> 00:03:43,110 at that point until they're an adult. 79 00:03:43,110 --> 00:03:47,280 So the goal is to really try 80 00:03:47,280 --> 00:03:51,390 to save that decision for the child 81 00:03:51,390 --> 00:03:54,270 to make when the child is of age to do that. 82 00:03:54,270 --> 00:03:57,840 The exceptions would be, and we'll talk about this shortly, 83 00:03:57,840 --> 00:04:01,560 but the exceptions will really be if it we're testing 84 00:04:01,560 --> 00:04:03,930 for a condition that the child is going 85 00:04:03,930 --> 00:04:08,930 to potentially manifest during their pediatric stage, 86 00:04:09,000 --> 00:04:12,930 or we could do something to affect the potential progression 87 00:04:12,930 --> 00:04:15,270 of a disease that might manifest later 88 00:04:15,270 --> 00:04:18,840 by having some kind of intervention early on. 89 00:04:18,840 --> 00:04:23,070 Adult genetic testing is a different consideration 90 00:04:23,070 --> 00:04:24,633 after pediatric because again, 91 00:04:25,728 --> 00:04:27,551 now you have the consideration of autonomy 92 00:04:27,551 --> 00:04:30,720 and an individual can decide for his or herself 93 00:04:30,720 --> 00:04:31,920 whether or not they would want 94 00:04:31,920 --> 00:04:33,690 to have a genetic test result. 95 00:04:33,690 --> 00:04:37,050 And we've been talking about this on the discussion board 96 00:04:37,050 --> 00:04:38,730 as well, I think some great conversations 97 00:04:38,730 --> 00:04:41,550 and just thinking about what would you want to do? 98 00:04:41,550 --> 00:04:44,370 And each patient certainly has the right 99 00:04:44,370 --> 00:04:46,320 to consider that for his or herself, 100 00:04:46,320 --> 00:04:49,200 whether or not they want to know what they want to know, 101 00:04:49,200 --> 00:04:51,090 when they want to know it. 102 00:04:51,090 --> 00:04:53,580 Because the difference between a genetic test result 103 00:04:53,580 --> 00:04:56,700 and, say, other kinds of lab results 104 00:04:56,700 --> 00:05:00,120 is that a genetic test result is for life. 105 00:05:00,120 --> 00:05:03,900 When you find out what your particular genetic makeup is 106 00:05:03,900 --> 00:05:05,640 for one gene or set of genes 107 00:05:05,640 --> 00:05:07,380 or even in the future in your whole genome, 108 00:05:07,380 --> 00:05:08,970 that's not going to change. 109 00:05:08,970 --> 00:05:12,240 So once you know it, you can't really unknow it. 110 00:05:12,240 --> 00:05:14,910 So it's important to really consider it carefully 111 00:05:14,910 --> 00:05:17,883 and for the patient to make that decision for themselves. 112 00:05:19,980 --> 00:05:21,750 Geriatric genetic testing 113 00:05:21,750 --> 00:05:24,150 is actually becoming much more common 114 00:05:24,150 --> 00:05:26,640 and it may provide useful information to the patient 115 00:05:26,640 --> 00:05:28,680 and their family. 116 00:05:28,680 --> 00:05:31,590 And however, common age-related conditions like dementia 117 00:05:31,590 --> 00:05:33,960 are not typically linked with alleles included 118 00:05:33,960 --> 00:05:35,640 in most genetic tests. 119 00:05:35,640 --> 00:05:37,530 So you may have some genetic testing 120 00:05:37,530 --> 00:05:41,460 that is actually helpful in, say, 121 00:05:41,460 --> 00:05:44,040 finding the right dose or the right drugs 122 00:05:44,040 --> 00:05:47,400 for if there's pharmacogenetic information that's known. 123 00:05:47,400 --> 00:05:49,510 Pharmacogenetics basically just means 124 00:05:50,370 --> 00:05:52,560 assessing a specific set of genes 125 00:05:52,560 --> 00:05:57,390 that are typically involved in metabolism of a drug, 126 00:05:57,390 --> 00:06:01,050 of a set of drugs using that to infer 127 00:06:01,050 --> 00:06:04,980 how a patient will respond to a drug therapy 128 00:06:04,980 --> 00:06:07,893 and the dosage of a drug therapy. 129 00:06:10,232 --> 00:06:13,350 It's not available for most drugs, certainly, 130 00:06:13,350 --> 00:06:14,820 but there are some 131 00:06:14,820 --> 00:06:18,870 that there is some good pharmacogenetic data available 132 00:06:18,870 --> 00:06:20,490 and some good tests that can be run 133 00:06:20,490 --> 00:06:24,930 to help determine ideal dosage or the dosage 134 00:06:24,930 --> 00:06:28,470 and drug selection that would be likely to be the safest 135 00:06:28,470 --> 00:06:30,794 and more effective in that particular individual. 136 00:06:30,794 --> 00:06:34,470 And so that's being used in geriatric population as well 137 00:06:34,470 --> 00:06:38,190 where there are certainly significant risks 138 00:06:38,190 --> 00:06:41,430 to the individual if they get the wrong drug 139 00:06:41,430 --> 00:06:42,633 or the wrong dose. 140 00:06:44,220 --> 00:06:45,660 So let's start at the beginning 141 00:06:45,660 --> 00:06:47,190 or actually before the beginning, 142 00:06:47,190 --> 00:06:49,440 preconception and prenatal testing. 143 00:06:49,440 --> 00:06:52,770 Preconception genetic counseling can be beneficial 144 00:06:52,770 --> 00:06:54,330 for those with a family history 145 00:06:54,330 --> 00:06:57,720 of a specific genetic disease or members of ethnicities 146 00:06:57,720 --> 00:07:00,228 or races with high risk of certain genetic diseases. 147 00:07:00,228 --> 00:07:04,110 We've spoken about the Ashkenazi Jewish population 148 00:07:04,110 --> 00:07:06,573 and that population in particular, 149 00:07:07,440 --> 00:07:09,600 there's a set of genetic diseases 150 00:07:09,600 --> 00:07:14,460 for which they typically have a higher carrier frequency 151 00:07:14,460 --> 00:07:16,080 than in the average population. 152 00:07:16,080 --> 00:07:20,970 And especially if you have both individuals in the couple 153 00:07:20,970 --> 00:07:22,290 that's considering having a child, 154 00:07:22,290 --> 00:07:25,740 if both of them are from the same race 155 00:07:25,740 --> 00:07:28,290 or ethnic group where you do have 156 00:07:28,290 --> 00:07:32,880 these higher frequencies of carriers, 157 00:07:32,880 --> 00:07:37,880 then it can be certainly advisable for that couple 158 00:07:38,580 --> 00:07:42,390 to seek genetic counseling just to better understand 159 00:07:42,390 --> 00:07:45,270 the risks and what, you know, 160 00:07:45,270 --> 00:07:47,433 what their options are moving forward. 161 00:07:48,480 --> 00:07:51,960 Preconception testing is usually for carrier status 162 00:07:51,960 --> 00:07:54,220 and because most likely 163 00:07:55,200 --> 00:07:58,200 by the time you're undergoing preconception counseling, 164 00:07:58,200 --> 00:07:59,580 we're talking about adults 165 00:07:59,580 --> 00:08:04,200 and if they wanted to have tested themselves 166 00:08:04,200 --> 00:08:06,060 for a genetic condition, they're concerned 167 00:08:06,060 --> 00:08:07,560 that they themselves will manifest. 168 00:08:07,560 --> 00:08:09,720 They would've already done it by now, most likely, 169 00:08:09,720 --> 00:08:12,150 not always, but most likely. 170 00:08:12,150 --> 00:08:14,730 But, so it's more likely to test for carrier status 171 00:08:14,730 --> 00:08:17,040 because you're not going to be symptomatic 172 00:08:17,040 --> 00:08:18,210 and you wouldn't really know 173 00:08:18,210 --> 00:08:20,163 unless you had this genetic test done. 174 00:08:21,000 --> 00:08:24,660 Prenatal testing typically focuses on testing the fetus 175 00:08:24,660 --> 00:08:27,840 for genetic disease or chromosomal abnormality. 176 00:08:27,840 --> 00:08:30,724 And this could be testing for specific genetic disease 177 00:08:30,724 --> 00:08:34,080 that's known to run in someone's family 178 00:08:34,080 --> 00:08:36,580 or that's more common in their ethnic group 179 00:08:37,530 --> 00:08:39,600 or those chromosomal abnormalities. 180 00:08:39,600 --> 00:08:42,333 And chromosomal abnormalities, as you remember, 181 00:08:44,120 --> 00:08:47,760 are actually typically a random event 182 00:08:47,760 --> 00:08:50,010 and unlikely to have been inherited, 183 00:08:50,010 --> 00:08:52,680 so unlikely to have run in the family, 184 00:08:52,680 --> 00:08:56,340 but most likely to have just happened rather spontaneously 185 00:08:56,340 --> 00:08:58,020 or as a random event. 186 00:08:58,020 --> 00:09:02,040 So in women or couples 187 00:09:02,040 --> 00:09:04,650 where you've had many, 188 00:09:04,650 --> 00:09:07,920 say you where there's been a higher incidence 189 00:09:07,920 --> 00:09:10,380 of spontaneous abortions 190 00:09:10,380 --> 00:09:11,920 or if they have had a child 191 00:09:13,020 --> 00:09:16,023 who has had a chromosomal abnormality, 192 00:09:16,890 --> 00:09:21,890 it's probably beneficial for them to undergo genetic testing 193 00:09:23,850 --> 00:09:26,400 if that's something the couple wants to know. 194 00:09:26,400 --> 00:09:29,463 As with any tests, of course, 195 00:09:30,488 --> 00:09:31,680 what we're talking about here 196 00:09:31,680 --> 00:09:36,480 is that the individual 197 00:09:36,480 --> 00:09:38,460 or the family members involved 198 00:09:38,460 --> 00:09:41,850 are all well-informed that they make a decision 199 00:09:41,850 --> 00:09:45,870 based upon that information and knowing what they will do 200 00:09:45,870 --> 00:09:48,300 with that information when the test result comes back. 201 00:09:48,300 --> 00:09:50,430 Same thing for the healthcare providers as well, 202 00:09:50,430 --> 00:09:52,130 knowing what are you going to do 203 00:09:52,130 --> 00:09:53,610 if the result comes back positive 204 00:09:53,610 --> 00:09:55,380 or negative or inconclusive 205 00:09:55,380 --> 00:09:58,953 and being informed before undergoing the test. 206 00:10:00,300 --> 00:10:02,130 Preconception results may inform 207 00:10:02,130 --> 00:10:04,290 or influence future reproductive decisions, 208 00:10:04,290 --> 00:10:06,630 while prenatal results may inform the decision 209 00:10:06,630 --> 00:10:09,300 to carry to term or help prepare the family 210 00:10:09,300 --> 00:10:11,280 for a child's future care. 211 00:10:11,280 --> 00:10:13,980 So again, when we're thinking about what are we going to do 212 00:10:13,980 --> 00:10:16,920 with this information, that's the part that needs 213 00:10:16,920 --> 00:10:19,230 to be filled in, if possible, 214 00:10:19,230 --> 00:10:22,620 with the information from the couple, 215 00:10:22,620 --> 00:10:25,410 the families, everybody involved 216 00:10:25,410 --> 00:10:28,500 to think through what are they going to do, 217 00:10:28,500 --> 00:10:30,480 depending upon the results that come back. 218 00:10:30,480 --> 00:10:32,130 And it still might not be enough 219 00:10:32,130 --> 00:10:35,040 to fully prepare them when the results come back, 220 00:10:35,040 --> 00:10:37,440 but at least they're starting to think about it 221 00:10:37,440 --> 00:10:39,090 and they're making an informed decision 222 00:10:39,090 --> 00:10:41,973 as to whether or not they wish to pursue those tests. 223 00:10:43,020 --> 00:10:45,870 Preconception and prenatal testing can both significantly 224 00:10:45,870 --> 00:10:49,260 impact the patient's emotional wellbeing and relationships. 225 00:10:49,260 --> 00:10:52,710 And this is of course, critical to keep in mind 226 00:10:52,710 --> 00:10:56,700 and as we've been talking about in the discussion boards, 227 00:10:56,700 --> 00:10:59,610 it really does kind of come down to a gut feeling 228 00:10:59,610 --> 00:11:02,550 of whether you do or do not want to know something 229 00:11:02,550 --> 00:11:05,760 and this is the same for prenatal 230 00:11:05,760 --> 00:11:07,200 or even preconception testing. 231 00:11:07,200 --> 00:11:09,390 Some people just will not want to know 232 00:11:09,390 --> 00:11:12,120 and it would be detrimental to their emotional wellbeing 233 00:11:12,120 --> 00:11:15,210 and potentially to their relationships if they do. 234 00:11:15,210 --> 00:11:18,270 So, thinking through it being very clear, 235 00:11:18,270 --> 00:11:20,580 especially going to see genetic counseling 236 00:11:20,580 --> 00:11:25,203 if at all possible, would be the best option. 237 00:11:27,240 --> 00:11:28,975 All right, so we're talking about tests here 238 00:11:28,975 --> 00:11:32,550 and I wanted to throw in a quick reminder 239 00:11:32,550 --> 00:11:35,010 if you've seen this before, hopefully you have, 240 00:11:35,010 --> 00:11:38,250 if not, the concept is relatively straightforward 241 00:11:38,250 --> 00:11:40,080 for our purposes here 242 00:11:40,080 --> 00:11:44,460 about a diagnostic sensitivity versus specificity. 243 00:11:44,460 --> 00:11:46,650 So we're gonna be talking about testing, 244 00:11:46,650 --> 00:11:50,610 but there's primarily, you can think of, 245 00:11:50,610 --> 00:11:52,470 broadly, two kinds of testing. 246 00:11:52,470 --> 00:11:56,400 One being more of a screen, which would be a screen 247 00:11:56,400 --> 00:11:59,040 would be looking at a large population 248 00:11:59,040 --> 00:12:01,890 and trying to identify individuals 249 00:12:01,890 --> 00:12:04,530 who are likely to have a disease 250 00:12:04,530 --> 00:12:07,980 or a condition out of the whole big population 251 00:12:07,980 --> 00:12:12,420 versus a diagnostic test where this is very likely 252 00:12:12,420 --> 00:12:16,020 to be a much smaller population where there's already reason 253 00:12:16,020 --> 00:12:18,630 to believe someone might have a condition, 254 00:12:18,630 --> 00:12:20,610 there's a suspicion of one sort or another, 255 00:12:20,610 --> 00:12:22,650 whether it's they're they're demonstrating 256 00:12:22,650 --> 00:12:24,090 some kind of signs or symptoms 257 00:12:24,090 --> 00:12:26,430 or there's risk factors associated 258 00:12:26,430 --> 00:12:28,950 with them that would increase the chance 259 00:12:28,950 --> 00:12:30,330 that they would have this condition 260 00:12:30,330 --> 00:12:31,773 or develop this condition. 261 00:12:33,300 --> 00:12:35,220 So you want to keep that in mind. 262 00:12:35,220 --> 00:12:39,630 And those kinds of tests then are very likely 263 00:12:39,630 --> 00:12:42,689 to positively identify those 264 00:12:42,689 --> 00:12:45,870 who indeed do have the condition, 265 00:12:45,870 --> 00:12:47,250 who indeed do have the condition. 266 00:12:47,250 --> 00:12:48,660 So we're talking about sensitivity 267 00:12:48,660 --> 00:12:50,560 and specificity as measures 268 00:12:51,780 --> 00:12:56,780 that are reported out for different diagnostics and screens. 269 00:12:56,970 --> 00:12:58,380 Sensitivity, you can think of 270 00:12:58,380 --> 00:13:00,120 as a measure of a test's ability 271 00:13:00,120 --> 00:13:03,360 to identify those at risk for a condition. 272 00:13:03,360 --> 00:13:06,753 So high sensitivity would be best for screening. 273 00:13:07,950 --> 00:13:10,830 Thinking of it as ruling out. 274 00:13:10,830 --> 00:13:15,830 So it's going to come back potentially with a group. 275 00:13:15,870 --> 00:13:18,660 So let's say we're starting with the whole population 276 00:13:18,660 --> 00:13:20,370 of the United States. 277 00:13:20,370 --> 00:13:23,400 Let's say there's 300, 278 00:13:23,400 --> 00:13:26,310 let's just say there's 300 million people in the US 279 00:13:26,310 --> 00:13:29,220 and we're screening every single one of them 280 00:13:29,220 --> 00:13:31,290 for a particular condition. 281 00:13:31,290 --> 00:13:34,530 And what comes back is that it comes back 282 00:13:34,530 --> 00:13:36,210 with 1% of the population. 283 00:13:36,210 --> 00:13:38,160 So 3 million people come back 284 00:13:38,160 --> 00:13:40,650 with a positive result on that screen. 285 00:13:40,650 --> 00:13:43,020 It doesn't mean all 3 million people 286 00:13:43,020 --> 00:13:45,720 have this condition we're screening for. 287 00:13:45,720 --> 00:13:48,180 What it does mean is that 288 00:13:48,180 --> 00:13:51,060 that really virtually no one 289 00:13:51,060 --> 00:13:54,240 in the remaining 297 million people 290 00:13:54,240 --> 00:13:57,180 who got a negative result for the screen, 291 00:13:57,180 --> 00:14:00,360 virtually none of them are actually positive. 292 00:14:00,360 --> 00:14:03,690 But in our group that came back as testing positive, 293 00:14:03,690 --> 00:14:06,930 there's likely quite a few who are actually negative, 294 00:14:06,930 --> 00:14:10,230 but they received a positive result on the screen. 295 00:14:10,230 --> 00:14:11,100 Why is this? 296 00:14:11,100 --> 00:14:13,900 Well, we want to have the highest sensitivity 297 00:14:14,790 --> 00:14:17,310 for a screen because we don't wanna miss anybody. 298 00:14:17,310 --> 00:14:19,680 We want to first narrow our group down, 299 00:14:19,680 --> 00:14:21,930 let's say now we're down to that 1% of the population. 300 00:14:21,930 --> 00:14:24,810 Okay, so now what can we do in that 1% of the population? 301 00:14:24,810 --> 00:14:27,060 Now we can check that each of them 302 00:14:27,060 --> 00:14:28,450 with one of these really 303 00:14:30,778 --> 00:14:33,120 high specificity tests, 304 00:14:33,120 --> 00:14:36,060 which is going to basically confirm 305 00:14:36,060 --> 00:14:39,900 or really give us a much more clear diagnosis 306 00:14:39,900 --> 00:14:42,720 that a person has a particular condition. 307 00:14:42,720 --> 00:14:46,380 So in a highly sensitive test, 308 00:14:46,380 --> 00:14:50,010 basically if you get a negative result, 309 00:14:50,010 --> 00:14:51,570 you can feel really confident 310 00:14:51,570 --> 00:14:53,640 that the person truly is negative, 311 00:14:53,640 --> 00:14:55,440 that they don't have this condition. 312 00:14:55,440 --> 00:14:58,410 And that's why we wanna use it for a screen. 313 00:14:58,410 --> 00:14:59,250 We're casting, you know, 314 00:14:59,250 --> 00:15:01,860 casting a wide net across the whole population 315 00:15:01,860 --> 00:15:03,810 to make sure that we're not missing anybody 316 00:15:03,810 --> 00:15:05,010 who actually has the condition. 317 00:15:05,010 --> 00:15:06,780 And then if that comes back positive, 318 00:15:06,780 --> 00:15:08,770 there's an immediate reflex test 319 00:15:10,120 --> 00:15:14,700 for a test with high specificity 320 00:15:14,700 --> 00:15:16,290 to confirm the results. 321 00:15:16,290 --> 00:15:18,960 So this would give low false positive. 322 00:15:18,960 --> 00:15:20,910 So now we're gonna take that reduced population 323 00:15:20,910 --> 00:15:22,500 that came back as positive from the screen, 324 00:15:22,500 --> 00:15:25,500 we're gonna test all of them with a different kind of test 325 00:15:25,500 --> 00:15:27,780 that's going to have high specificity 326 00:15:27,780 --> 00:15:30,330 so that we can feel confident that every one of those 327 00:15:30,330 --> 00:15:33,600 that comes back is positive, truly is positive, 328 00:15:33,600 --> 00:15:35,730 truly is positive, okay? 329 00:15:35,730 --> 00:15:39,660 So there's oftentimes there's several tests 330 00:15:39,660 --> 00:15:43,920 that are grouped together to confirm 331 00:15:43,920 --> 00:15:46,440 that an individual has a particular condition, 332 00:15:46,440 --> 00:15:50,160 especially if it's something like a condition 333 00:15:50,160 --> 00:15:52,653 that we're testing for in the broad population. 334 00:15:54,060 --> 00:15:57,600 Okay, so hopefully that's pretty clear. 335 00:15:57,600 --> 00:16:01,590 You can think of a high sensitivity test as a rule-out test. 336 00:16:01,590 --> 00:16:04,208 So we're trying to, 337 00:16:04,208 --> 00:16:06,630 everybody who tests negative, 338 00:16:06,630 --> 00:16:09,600 you can rule yourself out as having that condition. 339 00:16:09,600 --> 00:16:12,160 And high specificity test is a rule-in condition. 340 00:16:12,160 --> 00:16:14,550 So if it comes back positive, you can feel certain 341 00:16:14,550 --> 00:16:17,520 that that person truly is positive. 342 00:16:17,520 --> 00:16:19,650 Ideally, I mean, sure, in a perfect world, 343 00:16:19,650 --> 00:16:22,500 we would want all tests to be both highly sensitive 344 00:16:22,500 --> 00:16:24,030 and highly specific. 345 00:16:24,030 --> 00:16:27,960 The reality is that's very challenging 346 00:16:27,960 --> 00:16:31,050 and certainly is a goal of all diagnostics makers, 347 00:16:31,050 --> 00:16:35,583 but not something that can always be achieved. 348 00:16:37,680 --> 00:16:40,110 Okay, so thinking about some of the risks 349 00:16:40,110 --> 00:16:42,870 and cautions in prenatal testing and screening, 350 00:16:42,870 --> 00:16:44,550 false positives, so this indicates 351 00:16:44,550 --> 00:16:45,870 the fetus has a genetic disease 352 00:16:45,870 --> 00:16:48,300 or disorder when that is not the case. 353 00:16:48,300 --> 00:16:51,390 And false negatives, so that would be indicating the fetus 354 00:16:51,390 --> 00:16:52,920 does not have a genetic condition 355 00:16:52,920 --> 00:16:55,230 or disorder that is actually present, 356 00:16:55,230 --> 00:16:57,407 can occur with any genetic test or screen 357 00:16:57,407 --> 00:17:01,020 and must be explained as a possibility to the patient. 358 00:17:01,020 --> 00:17:03,090 So even if something comes back 359 00:17:03,090 --> 00:17:04,770 and it's saying it's positive 360 00:17:04,770 --> 00:17:08,970 or it's a negative result, usually with every diagnostic, 361 00:17:08,970 --> 00:17:11,880 they report back some kind 362 00:17:11,880 --> 00:17:14,190 of an indicator of the false positive 363 00:17:14,190 --> 00:17:16,050 and false negative rate, 364 00:17:16,050 --> 00:17:19,530 and that could be used to help explain those risks 365 00:17:19,530 --> 00:17:23,430 to the patient that's receiving this information. 366 00:17:23,430 --> 00:17:25,740 So all screens that return a positive result 367 00:17:25,740 --> 00:17:28,170 must be followed up with other clinical diagnostics 368 00:17:28,170 --> 00:17:29,940 to confirm, as we talked about, 369 00:17:29,940 --> 00:17:31,500 not just another genetic test, 370 00:17:31,500 --> 00:17:35,550 but also any other kind of diagnostics that can be used 371 00:17:35,550 --> 00:17:37,170 to compliment that, just to confirm 372 00:17:37,170 --> 00:17:40,230 that the positive result truly is positive. 373 00:17:40,230 --> 00:17:42,090 Some prenatal tests are invasive. 374 00:17:42,090 --> 00:17:44,490 So this is important to keep in mind. 375 00:17:44,490 --> 00:17:49,350 Amniocentesis and CVS in particular are, 376 00:17:49,350 --> 00:17:51,780 CVS in particular is quite invasive. 377 00:17:51,780 --> 00:17:55,140 And each of these types 378 00:17:55,140 --> 00:18:00,140 of procedures carries with it a risk of abortion 379 00:18:00,300 --> 00:18:02,340 that can happen, spontaneous abortion, 380 00:18:02,340 --> 00:18:07,050 miscarriage that can happen as a result of the test itself 381 00:18:07,050 --> 00:18:10,470 and that risk may not be acceptable 382 00:18:10,470 --> 00:18:12,333 to the patient who's considering it. 383 00:18:14,550 --> 00:18:17,430 All right, cell-free fetal DNA testing. 384 00:18:17,430 --> 00:18:19,780 So if we're trying to move past 385 00:18:20,769 --> 00:18:23,010 the time when we're using amnio 386 00:18:23,010 --> 00:18:26,940 and CVS to test prenatal samples, 387 00:18:26,940 --> 00:18:28,740 we're moving to a time where we're trying 388 00:18:28,740 --> 00:18:30,990 to be as non-invasive as possible. 389 00:18:30,990 --> 00:18:34,023 And this is called non-invasive prenatal testing or NIPT. 390 00:18:34,860 --> 00:18:37,830 It's a promising approach to prenatal genetic testing, 391 00:18:37,830 --> 00:18:39,150 reducing risk to the mother 392 00:18:39,150 --> 00:18:40,710 and fetus from invasive procedures. 393 00:18:40,710 --> 00:18:42,690 And basically all it requires 394 00:18:42,690 --> 00:18:45,000 is to draw blood sample from the mother 395 00:18:45,000 --> 00:18:48,870 and to sort out the fetal DNA from the mother's DNA. 396 00:18:48,870 --> 00:18:51,513 And it's really interesting, there's actually a, 397 00:18:53,130 --> 00:18:57,420 there's DNA that is basically sort of floating around 398 00:18:57,420 --> 00:19:01,860 in the amniotic fluid that then crosses the placenta 399 00:19:01,860 --> 00:19:03,300 and crosses into the mother, 400 00:19:03,300 --> 00:19:05,490 into the bloodstream of the mother. 401 00:19:05,490 --> 00:19:08,490 So there is some small, small amounts, 402 00:19:08,490 --> 00:19:11,370 very small amounts of fetal DNA, it's called cell-free 403 00:19:11,370 --> 00:19:13,650 because there aren't actually cells, 404 00:19:13,650 --> 00:19:16,020 whole cells from the fetus floating around, 405 00:19:16,020 --> 00:19:20,100 but it's DNA from the fetus is, again, 406 00:19:20,100 --> 00:19:21,940 small amount is floating around 407 00:19:22,800 --> 00:19:25,170 and circulating in the mother's blood. 408 00:19:25,170 --> 00:19:27,420 So if we take a blood draw from the mother 409 00:19:27,420 --> 00:19:30,660 and using molecular techniques can actually separate out 410 00:19:30,660 --> 00:19:33,330 the maternal from the fetal DNA, 411 00:19:33,330 --> 00:19:35,970 then what you could do is test that fetal DNA 412 00:19:35,970 --> 00:19:38,190 and see if what, you know, 413 00:19:38,190 --> 00:19:42,750 what conditions are present without ever having to invade 414 00:19:42,750 --> 00:19:46,290 into the uterus or take amniotic fluid 415 00:19:46,290 --> 00:19:48,840 or take a sample from the fetus itself 416 00:19:48,840 --> 00:19:52,140 without any of those invasive procedures. 417 00:19:52,140 --> 00:19:54,870 Basically, you're just taking a blood draw. 418 00:19:54,870 --> 00:19:58,680 So this really is the future of testing. 419 00:19:58,680 --> 00:20:02,040 Obviously it relies upon technologies to be able 420 00:20:02,040 --> 00:20:05,760 to reliably separate fetal DNA from the maternal DNA 421 00:20:05,760 --> 00:20:07,290 and that is a challenge, 422 00:20:07,290 --> 00:20:11,670 but that is absolutely the direction that testing is going. 423 00:20:11,670 --> 00:20:13,530 Newborn screening and genetic testing. 424 00:20:13,530 --> 00:20:16,950 So newborn screening, it's mandated by each state in the US 425 00:20:16,950 --> 00:20:18,570 and the Department of Health 426 00:20:18,570 --> 00:20:21,660 for each of those states is in charge 427 00:20:21,660 --> 00:20:24,840 of determining which conditions they're testing for 428 00:20:24,840 --> 00:20:26,820 and how it's managed. 429 00:20:26,820 --> 00:20:28,350 In the state of Vermont, parents have the right 430 00:20:28,350 --> 00:20:30,180 to refuse screening for any reason, 431 00:20:30,180 --> 00:20:34,200 however, they have to state that they are refusing screening 432 00:20:34,200 --> 00:20:39,180 otherwise the newborn will be screened. 433 00:20:39,180 --> 00:20:41,760 So they have to actively request that it not happen. 434 00:20:41,760 --> 00:20:43,320 They're not asked. 435 00:20:43,320 --> 00:20:45,750 Babies born at home, and the reason for that is 436 00:20:45,750 --> 00:20:48,780 because it's viewed as a public health issue. 437 00:20:48,780 --> 00:20:53,070 Because if you can catch these conditions early on, 438 00:20:53,070 --> 00:20:56,220 these conditions which often manifest very early, 439 00:20:56,220 --> 00:20:59,730 very soon after birth, they're commonly metabolic conditions 440 00:20:59,730 --> 00:21:02,700 that only manifest once the child starts feeding 441 00:21:02,700 --> 00:21:06,480 in many cases or they're conditions 442 00:21:06,480 --> 00:21:08,730 where early intervention would make a world 443 00:21:08,730 --> 00:21:10,530 of difference to the child. 444 00:21:10,530 --> 00:21:13,350 So these are biochemical tests 445 00:21:13,350 --> 00:21:14,580 that are done on the blood. 446 00:21:14,580 --> 00:21:19,580 You can see that in the picture in the top right corner, 447 00:21:19,800 --> 00:21:21,330 it's what's called a heel prick test. 448 00:21:21,330 --> 00:21:23,430 So the newborn's heel is pricked 449 00:21:23,430 --> 00:21:27,270 and the blood is collected on a card 450 00:21:27,270 --> 00:21:30,330 and that card is sent off to the lab and testing is done. 451 00:21:30,330 --> 00:21:32,970 It's usually biochemical type of testing on the blood 452 00:21:32,970 --> 00:21:35,300 to see if there's any abnormalities 453 00:21:35,300 --> 00:21:38,410 in the typical blood biochemistry that might be associated 454 00:21:39,667 --> 00:21:41,340 with certain conditions. 455 00:21:41,340 --> 00:21:44,490 Many of those conditions are genetic conditions, 456 00:21:44,490 --> 00:21:47,880 but this is not a genetic test per se. 457 00:21:47,880 --> 00:21:50,280 It's not actually a, 458 00:21:50,280 --> 00:21:53,040 not doing any sequencing here on the screen, 459 00:21:53,040 --> 00:21:55,680 they're just looking for biochemical abnormalities. 460 00:21:55,680 --> 00:21:57,360 And so this is a screen, remember, 461 00:21:57,360 --> 00:22:00,240 so we're looking at the whole population we're screening. 462 00:22:00,240 --> 00:22:03,540 And so when it comes back as positive, 463 00:22:03,540 --> 00:22:07,470 it may or may not actually be positive. 464 00:22:07,470 --> 00:22:10,230 If it comes back as negative, you can feel really confident 465 00:22:10,230 --> 00:22:13,590 that in fact the child does not have that condition. 466 00:22:13,590 --> 00:22:15,900 But if it comes back as positive, 467 00:22:15,900 --> 00:22:18,060 there's a reflex test that's done 468 00:22:18,060 --> 00:22:22,290 with a more highly specific diagnostic for that condition. 469 00:22:22,290 --> 00:22:25,350 Usually actual genetic sequencing that would be done, 470 00:22:25,350 --> 00:22:27,780 if it's a genetic condition, to confirm 471 00:22:27,780 --> 00:22:29,970 that in fact the child does have a genetic condition. 472 00:22:29,970 --> 00:22:33,810 So even if a screen comes back as positive for something, 473 00:22:33,810 --> 00:22:37,740 doesn't necessarily mean it's going to be positive 474 00:22:37,740 --> 00:22:41,610 by the time, you know, all the diagnostics come back in. 475 00:22:41,610 --> 00:22:42,720 Babies born at home, 476 00:22:42,720 --> 00:22:45,150 and this happens a lot in Vermont, 477 00:22:45,150 --> 00:22:48,900 babies born at home have newborn screening if requested 478 00:22:48,900 --> 00:22:50,973 by the parents in an office visit. 479 00:22:52,140 --> 00:22:54,720 And Vermont, so in the state of Vermont, 480 00:22:54,720 --> 00:22:57,090 we have 29 conditions in newborn screening. 481 00:22:57,090 --> 00:23:00,330 And you can find a list of those on the, 482 00:23:00,330 --> 00:23:03,450 there's a link to the Department of Health site 483 00:23:03,450 --> 00:23:05,520 in the reading folder, online resources 484 00:23:05,520 --> 00:23:08,400 for this week if you're interested in checking out 485 00:23:08,400 --> 00:23:11,403 the conditions that are tested for in the state of Vermont. 486 00:23:12,930 --> 00:23:16,290 So how do they decide which conditions go onto a list? 487 00:23:16,290 --> 00:23:18,450 And as I said, each state decides separately, 488 00:23:18,450 --> 00:23:19,350 there are some conditions 489 00:23:19,350 --> 00:23:21,510 that are tested for in every state, 490 00:23:21,510 --> 00:23:24,300 but there are other conditions that are not. 491 00:23:24,300 --> 00:23:29,300 And in general, the way screening is determined, 492 00:23:29,550 --> 00:23:31,080 whether or not they're going to screen 493 00:23:31,080 --> 00:23:34,740 for a condition is they use these criteria 494 00:23:34,740 --> 00:23:38,700 that were developed in the sixties actually from a group, 495 00:23:38,700 --> 00:23:41,250 from the World Health Organization, 496 00:23:41,250 --> 00:23:44,520 Wilson and Jungner screening criteria. 497 00:23:44,520 --> 00:23:47,790 And these would include assessing the condition 498 00:23:47,790 --> 00:23:51,480 for whether or not it is a serious health problem, 499 00:23:51,480 --> 00:23:54,540 whether there's accepted treatment available, 500 00:23:54,540 --> 00:23:58,980 if it can be diagnosed, if they're recognizable latent 501 00:23:58,980 --> 00:24:01,860 or early onset symptoms that can be addressed. 502 00:24:01,860 --> 00:24:04,950 There's a suitable test acceptable to the population. 503 00:24:04,950 --> 00:24:07,260 So all of these are really necessary 504 00:24:07,260 --> 00:24:08,400 if there isn't a suitable test 505 00:24:08,400 --> 00:24:10,320 and if it doesn't work in the population, 506 00:24:10,320 --> 00:24:13,260 it's not going to be something we can include in the screen. 507 00:24:13,260 --> 00:24:15,780 Is a well-understood natural history for the condition. 508 00:24:15,780 --> 00:24:18,510 So it's not something so rare 509 00:24:18,510 --> 00:24:21,780 that we don't even understand how the disease works. 510 00:24:21,780 --> 00:24:24,150 There's an agreed policy who is treated. 511 00:24:24,150 --> 00:24:26,880 So if it comes back positive, who would be treated. 512 00:24:26,880 --> 00:24:29,190 Cost of testing and treatment is balanced 513 00:24:29,190 --> 00:24:33,090 to the cost of treating the condition 514 00:24:33,090 --> 00:24:36,450 or testing for the condition individually. 515 00:24:36,450 --> 00:24:38,132 And that there's a continuing process 516 00:24:38,132 --> 00:24:40,560 of reassessment as new data, 517 00:24:40,560 --> 00:24:42,810 new treatment becomes available. 518 00:24:42,810 --> 00:24:46,560 So this is one way in which organizations 519 00:24:46,560 --> 00:24:48,780 and departments of health will assess 520 00:24:48,780 --> 00:24:50,670 and decide which conditions are included 521 00:24:50,670 --> 00:24:52,023 in newborn screening. 522 00:24:53,700 --> 00:24:55,080 So the future of newborn screening 523 00:24:55,080 --> 00:24:57,630 with whole genome sequencing becoming readily available 524 00:24:57,630 --> 00:24:59,370 and cost-effective, the possibility 525 00:24:59,370 --> 00:25:01,590 of newborn genome screening becomes, 526 00:25:01,590 --> 00:25:04,320 or newborn genome sequencing rather becomes real. 527 00:25:04,320 --> 00:25:07,620 So this is an interesting idea, right? 528 00:25:07,620 --> 00:25:10,950 So instead of just testing for one thing at a time, 529 00:25:10,950 --> 00:25:14,340 doing one genetic test at a time, 530 00:25:14,340 --> 00:25:16,200 let's just sequence the entire genome 531 00:25:16,200 --> 00:25:17,750 right from the moment of birth. 532 00:25:18,810 --> 00:25:20,070 Well, it's an interesting idea 533 00:25:20,070 --> 00:25:23,250 and for some it may, it may seem like, well, 534 00:25:23,250 --> 00:25:24,507 this is perfectly logical, let's do that. 535 00:25:24,507 --> 00:25:27,660 And for others it may make you feel queasy 536 00:25:27,660 --> 00:25:30,870 to think about that as, you know, 537 00:25:30,870 --> 00:25:34,950 we've talked about autonomy and the right 538 00:25:34,950 --> 00:25:38,160 to make a decision for yourself as to what information 539 00:25:38,160 --> 00:25:39,570 you do and do not want to know. 540 00:25:39,570 --> 00:25:44,160 Privacy becomes a real question and finding out information 541 00:25:44,160 --> 00:25:46,170 about which we can really do nothing 542 00:25:46,170 --> 00:25:49,350 and whether that's valuable or not. 543 00:25:49,350 --> 00:25:52,260 So there are lots of questions to consider here, 544 00:25:52,260 --> 00:25:55,980 but there are a few health centers that are piloting this, 545 00:25:55,980 --> 00:25:58,570 large health centers that are piloting this 546 00:25:59,490 --> 00:26:02,610 and it's, you know, it's tough to say right now 547 00:26:02,610 --> 00:26:05,250 whether that's the direction we're going to end up going, 548 00:26:05,250 --> 00:26:08,640 but certainly we don't have enough information 549 00:26:08,640 --> 00:26:11,400 to be able to interpret whole genomes 550 00:26:11,400 --> 00:26:14,670 to know what to do with all of that information yet. 551 00:26:14,670 --> 00:26:19,670 So I don't see it on the five-year horizon certainly, 552 00:26:19,950 --> 00:26:23,010 but looking out beyond that 10, 15, 20 years from now, 553 00:26:23,010 --> 00:26:25,170 it is absolutely a possibility. 554 00:26:25,170 --> 00:26:28,530 And I believe we would need to have 555 00:26:28,530 --> 00:26:31,650 a significant amount of policy in place 556 00:26:31,650 --> 00:26:35,010 and clear clinical guidelines, 557 00:26:35,010 --> 00:26:39,780 clear privacy measures to set up to address those concerns 558 00:26:39,780 --> 00:26:42,120 before we would move forward with this. 559 00:26:42,120 --> 00:26:43,720 That would certainly be my hope. 560 00:26:45,030 --> 00:26:48,810 So let's hope that that's how it works 561 00:26:48,810 --> 00:26:51,123 if it does move in that direction. 562 00:26:52,200 --> 00:26:55,500 So now let's move up into a little bit older timeframe. 563 00:26:55,500 --> 00:26:57,750 Now we're talking about pediatric genetics. 564 00:26:57,750 --> 00:26:59,910 So children presenting with symptoms consistent 565 00:26:59,910 --> 00:27:02,610 with a genetic disease may, with parental consent, 566 00:27:02,610 --> 00:27:05,730 undergo genetic testing to aid in diagnosis. 567 00:27:05,730 --> 00:27:09,480 So if a child is complaining, has symptoms, issues, 568 00:27:09,480 --> 00:27:11,490 again, we mentioned intellectual disability 569 00:27:11,490 --> 00:27:15,630 as a common red flag of a genetic disease in pediatric, 570 00:27:15,630 --> 00:27:18,720 which often shows up in pediatric population 571 00:27:18,720 --> 00:27:20,730 as opposed to any earlier than that. 572 00:27:20,730 --> 00:27:21,563 So, 573 00:27:23,774 --> 00:27:25,740 this would certainly raise the possibility 574 00:27:25,740 --> 00:27:27,690 for genetic testing to aid in diagnosis, 575 00:27:27,690 --> 00:27:32,010 which would potentially lead to better informed treatment. 576 00:27:32,010 --> 00:27:34,020 The American Academy of Pediatrics recommends 577 00:27:34,020 --> 00:27:36,570 the principle factor in making the decision 578 00:27:36,570 --> 00:27:38,040 for genetic testing is whether 579 00:27:38,040 --> 00:27:41,040 it is in the best interest of the child. 580 00:27:41,040 --> 00:27:42,390 Of the child, and I think of course, 581 00:27:42,390 --> 00:27:45,060 that that's always the best way to go. 582 00:27:45,060 --> 00:27:47,550 Predictive genetic testing is only recommended 583 00:27:47,550 --> 00:27:49,110 for those diseases with onset 584 00:27:49,110 --> 00:27:51,690 or possible intervention during childhood 585 00:27:51,690 --> 00:27:54,510 with parental consent and when possible 586 00:27:54,510 --> 00:27:56,680 with child consent to best inform the child 587 00:27:57,778 --> 00:28:00,780 and you know, if they're, say, in their teenage years, 588 00:28:00,780 --> 00:28:03,870 it may be possible for them to make an informed decision 589 00:28:03,870 --> 00:28:06,300 or to help in that informed decision. 590 00:28:06,300 --> 00:28:08,310 Adult onset predictive disease testing 591 00:28:08,310 --> 00:28:10,920 is not generally deemed to be the best interest 592 00:28:10,920 --> 00:28:14,220 of the child, again, to try to retain autonomy 593 00:28:14,220 --> 00:28:15,930 so that the child can make that decision 594 00:28:15,930 --> 00:28:17,910 for his or herself in the future. 595 00:28:17,910 --> 00:28:20,610 And certainly carrier status is almost universally 596 00:28:20,610 --> 00:28:24,000 not pursued in children as it's only relevant 597 00:28:24,000 --> 00:28:26,310 for family planning for the individual. 598 00:28:26,310 --> 00:28:28,230 So let that individual make that decision 599 00:28:28,230 --> 00:28:31,113 for themselves when they're of age to be able to do that. 600 00:28:33,210 --> 00:28:34,980 Okay, let's move on up to adults. 601 00:28:34,980 --> 00:28:36,930 So in adults we have genetic diseases 602 00:28:36,930 --> 00:28:40,020 with adult onset may be tested for in the adult population 603 00:28:40,020 --> 00:28:41,910 in those who have a family history 604 00:28:41,910 --> 00:28:43,710 and have decided to do so. 605 00:28:43,710 --> 00:28:46,530 Often they're sent to genetic counseling 606 00:28:46,530 --> 00:28:48,570 to best understand their risks 607 00:28:48,570 --> 00:28:51,960 and to talk through what are the possible options 608 00:28:51,960 --> 00:28:53,580 for testing, what are the results, 609 00:28:53,580 --> 00:28:55,350 what are the implications, 610 00:28:55,350 --> 00:28:58,380 and just to make sure everyone's well-informed 611 00:28:58,380 --> 00:28:59,910 before they make a decision. 612 00:28:59,910 --> 00:29:00,743 Huntington's disease, 613 00:29:00,743 --> 00:29:03,390 which we've talked about a decent amount in this class, 614 00:29:03,390 --> 00:29:05,790 is an autosomal dominant neurodegenerative disease 615 00:29:05,790 --> 00:29:08,130 a patient may choose to be tested for 616 00:29:08,130 --> 00:29:09,540 if one of his or her parents 617 00:29:09,540 --> 00:29:11,970 or grandparents had Huntington's disease. 618 00:29:11,970 --> 00:29:15,480 But as we talked about last week, I believe that, 619 00:29:15,480 --> 00:29:20,130 you know, if a grandparent has Huntington's disease 620 00:29:20,130 --> 00:29:23,070 and let's say an individual, 621 00:29:23,070 --> 00:29:28,070 that individual wants to be tested, but their parent, 622 00:29:28,200 --> 00:29:30,900 let's say it was their maternal grandfather 623 00:29:30,900 --> 00:29:32,790 who had Huntington's disease, 624 00:29:32,790 --> 00:29:35,100 and then their mother does not want to know 625 00:29:35,100 --> 00:29:37,770 whether or not she has Huntington's disease, 626 00:29:37,770 --> 00:29:39,300 but the child comes of age 627 00:29:39,300 --> 00:29:41,940 and decides that that he wants to know 628 00:29:41,940 --> 00:29:43,440 so he undergoes genetic testing 629 00:29:43,440 --> 00:29:46,110 and finds out he is positive for Huntington's disease, 630 00:29:46,110 --> 00:29:47,880 then he knows his mother 631 00:29:47,880 --> 00:29:49,560 also has Huntington's disease 632 00:29:49,560 --> 00:29:52,740 despite the fact that she did not agree 633 00:29:52,740 --> 00:29:54,780 or decide to have that test done. 634 00:29:54,780 --> 00:29:56,280 So there's a lot of complicating factors, 635 00:29:56,280 --> 00:29:57,113 but you know, at the same time, 636 00:29:57,113 --> 00:29:59,190 we can't restrict the right of that individual 637 00:29:59,190 --> 00:30:01,830 to have his genetic testing done. 638 00:30:01,830 --> 00:30:04,950 Once he's an adult, he can decide that for himself. 639 00:30:04,950 --> 00:30:09,240 So there's a balance that has to be sought 640 00:30:09,240 --> 00:30:12,570 whenever we're talking about these ethical situations 641 00:30:12,570 --> 00:30:14,910 and trying to maintain autonomy 642 00:30:14,910 --> 00:30:18,360 and informed consent for everyone involved. 643 00:30:18,360 --> 00:30:22,020 But it's almost impossible in every situation to do that. 644 00:30:22,020 --> 00:30:25,380 So cancer predisposition testing may be recommended 645 00:30:25,380 --> 00:30:27,150 for those with the family history of cancer 646 00:30:27,150 --> 00:30:29,400 or red flags of heritable cancer risk. 647 00:30:29,400 --> 00:30:34,320 And again, they'd likely be sent to genetic counseling 648 00:30:34,320 --> 00:30:37,680 and take a really complete family history, 649 00:30:37,680 --> 00:30:40,470 pedigree analysis, and assess 650 00:30:40,470 --> 00:30:42,450 what genetic tests are available 651 00:30:42,450 --> 00:30:45,753 for the inheritable forms of cancer. 652 00:30:47,070 --> 00:30:49,110 Carrier status may be tested in 653 00:30:49,110 --> 00:30:51,540 those planning to have children 654 00:30:51,540 --> 00:30:55,320 so that way it could help to inform their decisions 655 00:30:55,320 --> 00:30:57,840 about whether or not they want 656 00:30:57,840 --> 00:31:02,130 to pursue having children biologically or if, you know, 657 00:31:02,130 --> 00:31:04,440 it may inform the kind of testing they would want 658 00:31:04,440 --> 00:31:06,760 to have done in prenatal testing 659 00:31:07,830 --> 00:31:11,040 or it can also just help them to better prepare 660 00:31:11,040 --> 00:31:12,840 for the possibility of having a child 661 00:31:12,840 --> 00:31:14,673 with certain conditions. 662 00:31:16,350 --> 00:31:19,080 Okay, moving to the geriatric population, 663 00:31:19,080 --> 00:31:22,140 Alzheimer's disease, age-related macular degeneration, 664 00:31:22,140 --> 00:31:24,330 and cancer are common age-related diseases 665 00:31:24,330 --> 00:31:26,160 with a demonstrated genetic component. 666 00:31:26,160 --> 00:31:28,950 So there certainly is rationale for testing 667 00:31:28,950 --> 00:31:31,650 for these conditions in geriatric population. 668 00:31:31,650 --> 00:31:33,840 There's also a rationale for testing, 669 00:31:33,840 --> 00:31:36,690 let's say if someone in the geriatric population 670 00:31:36,690 --> 00:31:39,513 develops age-related macular degeneration, 671 00:31:40,980 --> 00:31:44,340 there may be reason to have them tested, 672 00:31:44,340 --> 00:31:47,970 undergo genetic testing, even though that won't inform 673 00:31:47,970 --> 00:31:49,953 that treatment for that person, 674 00:31:51,060 --> 00:31:54,990 it could help to inform any of their relatives 675 00:31:54,990 --> 00:31:58,530 about their potential risk if it's genetic. 676 00:31:58,530 --> 00:32:03,450 So say an elderly patient comes in with macular degeneration 677 00:32:03,450 --> 00:32:06,360 and the thought is, okay, we could do genetic testing 678 00:32:06,360 --> 00:32:10,080 to see if the reason for, or part of the contribution, 679 00:32:10,080 --> 00:32:12,210 for this macular degeneration is genetic, 680 00:32:12,210 --> 00:32:13,650 it comes back positive, 681 00:32:13,650 --> 00:32:17,970 then that individual can inform their relatives 682 00:32:17,970 --> 00:32:20,160 of their potential risk of it as well. 683 00:32:20,160 --> 00:32:21,709 And they may undergo genetic testing 684 00:32:21,709 --> 00:32:26,580 to see if they also have the alleles 685 00:32:26,580 --> 00:32:28,320 for those diseases. 686 00:32:28,320 --> 00:32:32,730 So it may not be directly helpful for the health 687 00:32:32,730 --> 00:32:34,740 of the person who's getting the test, 688 00:32:34,740 --> 00:32:36,960 but it can help inform the health 689 00:32:36,960 --> 00:32:41,583 and potential future testing of other folks in their family. 690 00:32:43,110 --> 00:32:45,780 Alzheimer's disease genetic testing is restricted 691 00:32:45,780 --> 00:32:48,330 to select alleles demonstrated to contribute 692 00:32:48,330 --> 00:32:50,190 to early onset Alzheimer's disease, 693 00:32:50,190 --> 00:32:54,750 not late onset Alzheimer's disease or late onset dementia. 694 00:32:54,750 --> 00:32:58,830 So that's really more for developing Alzheimer's disease 695 00:32:58,830 --> 00:33:00,993 before the age of 65. 696 00:33:02,190 --> 00:33:05,850 There is a pretty substantial amount of data to support, 697 00:33:05,850 --> 00:33:07,680 there's a genetic component there. 698 00:33:07,680 --> 00:33:10,560 And again, if someone develops Alzheimer's disease, 699 00:33:10,560 --> 00:33:15,000 say at 58, 60 years old, it may not help them 700 00:33:15,000 --> 00:33:16,830 to have genetic testing directly, 701 00:33:16,830 --> 00:33:19,890 but it could help to inform their family members 702 00:33:19,890 --> 00:33:23,620 of their potential risk for Alzheimer's disease 703 00:33:24,568 --> 00:33:26,568 from an increased genetic risk, that is. 704 00:33:28,260 --> 00:33:32,640 All right, so some of the results that can come back, 705 00:33:32,640 --> 00:33:34,680 you might just think, well, it's gonna be positive 706 00:33:34,680 --> 00:33:35,640 or it's gonna be negative. 707 00:33:35,640 --> 00:33:36,750 They're gonna say, "Yes, you do," 708 00:33:36,750 --> 00:33:38,490 or, "No, you do not have it." 709 00:33:38,490 --> 00:33:43,050 Unfortunately, there is a third possibility for a result 710 00:33:43,050 --> 00:33:47,430 and this is not uncommon, not uncommon at all 711 00:33:47,430 --> 00:33:50,700 to get this result, which is the VUS, 712 00:33:50,700 --> 00:33:53,100 variant of unknown significance. 713 00:33:53,100 --> 00:33:54,090 What is that? 714 00:33:54,090 --> 00:33:57,700 Well, it's basically means we don't know 715 00:33:59,428 --> 00:34:01,710 what that person's sequence is going 716 00:34:01,710 --> 00:34:04,560 to indicate in terms of disease or not. 717 00:34:04,560 --> 00:34:08,853 So it means that they sequenced someone's allele, 718 00:34:10,032 --> 00:34:12,570 you know, of a gene that's associated 719 00:34:12,570 --> 00:34:16,230 with a particular disease or condition and it comes back 720 00:34:16,230 --> 00:34:18,270 and the sequence is not wild type. 721 00:34:18,270 --> 00:34:20,400 It's not one of the typical wild type sequences 722 00:34:20,400 --> 00:34:24,450 that we commonly see in the population of healthy folks, 723 00:34:24,450 --> 00:34:26,850 but it's also not one of the alleles known 724 00:34:26,850 --> 00:34:28,653 to cause this disease. 725 00:34:29,910 --> 00:34:32,899 So what do you do with that information? 726 00:34:32,899 --> 00:34:34,950 It's a change in the sequence 727 00:34:34,950 --> 00:34:36,630 and it would have to be a change in the sequence 728 00:34:36,630 --> 00:34:40,830 that would result in an amino acid substitution or, 729 00:34:40,830 --> 00:34:42,060 so it would either have to be a missense 730 00:34:42,060 --> 00:34:43,860 or nonsense mutation. 731 00:34:43,860 --> 00:34:47,460 So not just a silent mutation because we have tons of those 732 00:34:47,460 --> 00:34:49,290 and they don't matter effectively 733 00:34:49,290 --> 00:34:52,170 because it doesn't affect the amino acid 734 00:34:52,170 --> 00:34:54,660 that's coded for, right? 735 00:34:54,660 --> 00:34:56,610 So that's not really what we're talking about here. 736 00:34:56,610 --> 00:35:00,030 We're talking about a missense or nonsense mutation. 737 00:35:00,030 --> 00:35:03,090 Usually a missense mutation is what we're seeing 738 00:35:03,090 --> 00:35:05,580 and it's unclear as to whether or not 739 00:35:05,580 --> 00:35:06,930 that could result in the disease. 740 00:35:06,930 --> 00:35:08,280 So then you would get a result of 741 00:35:08,280 --> 00:35:10,650 it's a variant of unknown significance. 742 00:35:10,650 --> 00:35:12,720 We can't tell right now. 743 00:35:12,720 --> 00:35:13,950 And it can be really confusing 744 00:35:13,950 --> 00:35:16,410 and frustrating for a patient who's anticipating coming 745 00:35:16,410 --> 00:35:18,240 into the office and getting an answer. 746 00:35:18,240 --> 00:35:20,700 They probably paid, you know, a decent amount of money 747 00:35:20,700 --> 00:35:23,310 for the test, had to wait six, 748 00:35:23,310 --> 00:35:24,780 eight weeks to get the results. 749 00:35:24,780 --> 00:35:26,040 And they go in to hear 750 00:35:26,040 --> 00:35:29,340 and they're expecting to hear, yes, you do, no, you don't. 751 00:35:29,340 --> 00:35:32,190 Well, the third option is that it could be we don't know. 752 00:35:33,360 --> 00:35:36,390 And the only thing we can really say to this 753 00:35:36,390 --> 00:35:38,760 is that future research may link 754 00:35:38,760 --> 00:35:40,920 that variant to a specific risk, 755 00:35:40,920 --> 00:35:43,020 but as of today, there's no clear way 756 00:35:43,020 --> 00:35:44,430 to interpret those results. 757 00:35:44,430 --> 00:35:47,790 It could be that it does increase the risk 758 00:35:47,790 --> 00:35:51,120 for this condition or it could just be a perfectly finely 759 00:35:51,120 --> 00:35:53,640 functioning protein with no real issues 760 00:35:53,640 --> 00:35:56,550 and it's not going to result in the disease at all. 761 00:35:56,550 --> 00:35:57,960 And it's just a sequence 762 00:35:57,960 --> 00:36:01,080 that we just haven't come across yet until now, 763 00:36:01,080 --> 00:36:03,060 but we don't really have a better way 764 00:36:03,060 --> 00:36:04,080 to interpret it than that. 765 00:36:04,080 --> 00:36:05,910 And it can be really frustrating as you can imagine, 766 00:36:05,910 --> 00:36:07,510 for patients to get that result. 767 00:36:10,170 --> 00:36:11,640 So is this a good idea? 768 00:36:11,640 --> 00:36:15,030 Reported outcomes in patients following genetic testing: 769 00:36:15,030 --> 00:36:17,820 so BRCA1/2, there's been reported 770 00:36:17,820 --> 00:36:19,953 there's a temporary stress relieved, 771 00:36:23,820 --> 00:36:27,060 temporary stress relieved long-term, 772 00:36:27,060 --> 00:36:29,640 increased surveillance and general improvement 773 00:36:29,640 --> 00:36:32,340 to health long-term in most patients. 774 00:36:32,340 --> 00:36:34,950 So while it might result in the temporary stress, 775 00:36:34,950 --> 00:36:37,290 that is relieved in the longer term, 776 00:36:37,290 --> 00:36:41,700 and that in general does result in better surveillance, 777 00:36:41,700 --> 00:36:45,270 general improvement to long-term health in most patients 778 00:36:45,270 --> 00:36:46,710 who come back with a positive result 779 00:36:46,710 --> 00:36:48,660 for the BRCA1/2 test. 780 00:36:48,660 --> 00:36:51,510 Alzheimer's disease, neutral to slightly positive impact 781 00:36:51,510 --> 00:36:54,720 on psychological health, long-term for those who decide 782 00:36:54,720 --> 00:36:55,920 that they want to have the test 783 00:36:55,920 --> 00:36:57,810 and it comes back positive. 784 00:36:57,810 --> 00:37:00,310 For Huntington's disease, short-term in the seven 785 00:37:01,212 --> 00:37:05,040 to 10 days post results impact worsens depression scores 786 00:37:05,040 --> 00:37:07,053 for those who test positive, 787 00:37:07,950 --> 00:37:10,500 but depression scores improve long-term 788 00:37:10,500 --> 00:37:13,200 for those who test positive and negative. 789 00:37:13,200 --> 00:37:15,900 So if you take the population as a whole, 790 00:37:15,900 --> 00:37:17,460 that's how it averages out. 791 00:37:17,460 --> 00:37:19,980 I will just caution to say, you know, 792 00:37:19,980 --> 00:37:21,870 whenever we're talking about the psychological 793 00:37:21,870 --> 00:37:24,990 or psychosocial impact of anything, 794 00:37:24,990 --> 00:37:27,120 of course each individual has to be considered 795 00:37:27,120 --> 00:37:29,970 in their own context, in their own lives, 796 00:37:29,970 --> 00:37:31,380 in their own wishes. 797 00:37:31,380 --> 00:37:34,110 Because while this, again, this is taken as an average 798 00:37:34,110 --> 00:37:37,230 of the population, that doesn't mean 799 00:37:37,230 --> 00:37:40,590 that for each person it's going to turn out this way. 800 00:37:40,590 --> 00:37:45,590 So, you know, as always, their wishes, their interests, 801 00:37:45,630 --> 00:37:47,910 their understanding of their own situation 802 00:37:47,910 --> 00:37:51,300 is what's most important to consider. 803 00:37:51,300 --> 00:37:53,580 But if we do take the population as a whole, 804 00:37:53,580 --> 00:37:56,130 what we see generally is that 805 00:37:56,130 --> 00:38:00,180 even if the result comes back positive people are 806 00:38:00,180 --> 00:38:02,220 at least no worse off psychologically 807 00:38:02,220 --> 00:38:04,620 and potentially slightly better off psychologically 808 00:38:04,620 --> 00:38:07,680 and may be more proactive in their health, 809 00:38:07,680 --> 00:38:09,630 especially when it's something like BRCA1/2 810 00:38:09,630 --> 00:38:12,210 where they can actually do something about it. 811 00:38:12,210 --> 00:38:16,233 Like going and getting more surveillance, breast exams, 812 00:38:18,485 --> 00:38:20,760 and really taking more of an active role 813 00:38:20,760 --> 00:38:23,313 in preventing breast cancer and ovarian cancer. 814 00:38:26,340 --> 00:38:28,950 Okay, so again, considering all possible outcomes 815 00:38:28,950 --> 00:38:30,840 from a test, negative, positive, 816 00:38:30,840 --> 00:38:32,820 and that third one, the unknown 817 00:38:32,820 --> 00:38:35,730 and their impact on the approach to patient's care, 818 00:38:35,730 --> 00:38:37,920 so what are you going to do differently? 819 00:38:37,920 --> 00:38:39,510 What are other healthcare providers going 820 00:38:39,510 --> 00:38:41,340 to do differently with that information? 821 00:38:41,340 --> 00:38:43,620 Positive or negative lifestyle changes, 822 00:38:43,620 --> 00:38:45,990 patient's psychological and emotional welfare. 823 00:38:45,990 --> 00:38:48,810 Where are they now? Where might this lead them? 824 00:38:48,810 --> 00:38:50,790 Patients' family and or social group 825 00:38:50,790 --> 00:38:52,680 and their support structure, 826 00:38:52,680 --> 00:38:55,410 their understanding of their own health and wellbeing, 827 00:38:55,410 --> 00:38:58,060 and the patient's healthcare coverage and employment. 828 00:38:58,980 --> 00:39:00,980 These are all important to keep in mind. 829 00:39:02,040 --> 00:39:04,830 So what will the question really comes down to, 830 00:39:04,830 --> 00:39:07,350 what will you, the patient's healthcare team 831 00:39:07,350 --> 00:39:09,690 and/or the patient do differently in response 832 00:39:09,690 --> 00:39:13,470 to each of all possible test result outcomes? 833 00:39:13,470 --> 00:39:15,930 And this is commonly what a genetic counselor 834 00:39:15,930 --> 00:39:20,070 will walk through with a patient and their family members 835 00:39:20,070 --> 00:39:21,060 and just thinking through 836 00:39:21,060 --> 00:39:22,380 what are we gonna do if it's positive? 837 00:39:22,380 --> 00:39:24,540 What if it's negative? What if it's inconclusive? 838 00:39:24,540 --> 00:39:26,940 And make sure they've thought through everything 839 00:39:26,940 --> 00:39:30,393 before they make a decision on pursuing a test. 840 00:39:31,860 --> 00:39:33,990 So in summary, all stages of life, 841 00:39:33,990 --> 00:39:36,390 genetic testing requires careful consideration 842 00:39:36,390 --> 00:39:38,400 of all possible implications of results 843 00:39:38,400 --> 00:39:40,080 for the patient and their family. 844 00:39:40,080 --> 00:39:42,030 Decisions and actions that may be informed 845 00:39:42,030 --> 00:39:44,400 or influenced by genetic test results differ depending 846 00:39:44,400 --> 00:39:45,780 on the life stage, 847 00:39:45,780 --> 00:39:48,030 and advances in genetic testing technologies. 848 00:39:48,030 --> 00:39:50,250 And interpretation of results must be approached 849 00:39:50,250 --> 00:39:52,200 with great care for the ethical, social, 850 00:39:52,200 --> 00:39:54,870 and legal implications these results can have 851 00:39:54,870 --> 00:39:57,513 on the patient as a whole person. 852 00:39:58,530 --> 00:40:02,880 Okay, well that wraps it up here and in the next week, 853 00:40:02,880 --> 00:40:05,613 so once we're wrapped up this module, 854 00:40:07,950 --> 00:40:09,330 we're going to start diving into 855 00:40:09,330 --> 00:40:12,930 some more advanced clinical topics related to genetics 856 00:40:12,930 --> 00:40:15,240 and genomics in these emerging fields 857 00:40:15,240 --> 00:40:18,270 and give you a taste for a variety 858 00:40:18,270 --> 00:40:21,333 of different areas more specifically. 859 00:40:22,200 --> 00:40:24,120 And we're going to start that off next week 860 00:40:24,120 --> 00:40:26,130 with immunogenetics. 861 00:40:26,130 --> 00:40:29,310 Well, thank you very much for listening to this lecture 862 00:40:29,310 --> 00:40:31,050 and I look forward to talking 863 00:40:31,050 --> 00:40:32,460 with you on the discussion board. 864 00:40:32,460 --> 00:40:33,513 Take care. Bye.