1 00:00:02,536 --> 00:00:03,369 [Instructor] In this lecture, 2 00:00:03,369 --> 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, and 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 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 --> 00:01:13,110 or preconception genetic testing, it's typically recommended 26 00:01:13,110 --> 00:01:15,690 for specific diseases known to exist 27 00:01:15,690 --> 00:01:17,310 in the mother or father's family history. 28 00:01:17,310 --> 00:01:19,230 So this is where we'd be thinking, 29 00:01:19,230 --> 00:01:21,060 well, you might be a carrier 30 00:01:21,060 --> 00:01:24,630 for certain rare genetic diseases, for example, 31 00:01:24,630 --> 00:01:28,350 if there is a history of it in one or both 32 00:01:28,350 --> 00:01:33,300 of the individual's family histories 33 00:01:33,300 --> 00:01:37,650 in the couple that's considering having a child. 34 00:01:37,650 --> 00:01:40,890 And this is also true not just with if you have 35 00:01:40,890 --> 00:01:42,900 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 --> 00:02:15,453 and includes tests for genetic diseases. 46 00:02:16,950 --> 00:02:19,950 These are not genetic tests necessarily. 47 00:02:19,950 --> 00:02:21,780 They're typically biochemical tests 48 00:02:21,780 --> 00:02:24,870 that are performed on the blood sample 49 00:02:24,870 --> 00:02:28,500 that's taken shortly after birth, 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 --> 00:02:33,840 but they're just more so looking for the biochemistry 52 00:02:33,840 --> 00:02:36,780 that you would be able to assess in the blood, 53 00:02:36,780 --> 00:02:39,900 and that would be indicative of a high likelihood 54 00:02:39,900 --> 00:02:43,290 that an individual has a particular genetic condition. 55 00:02:43,290 --> 00:02:45,120 So, as we'll talk about shortly, 56 00:02:45,120 --> 00:02:47,880 that would always be followed up with a reflex test, 57 00:02:47,880 --> 00:02:48,750 what's called a reflex test. 58 00:02:48,750 --> 00:02:52,090 So if it comes back positive in a screen 59 00:02:53,550 --> 00:02:54,870 for a biochemical test, 60 00:02:54,870 --> 00:02:59,010 it would immediately go for more of a specific genetic test. 61 00:02:59,010 --> 00:03:00,810 Pediatric genetic testing occurs 62 00:03:00,810 --> 00:03:03,330 in children demonstrating possible symptoms 63 00:03:03,330 --> 00:03:05,970 of a genetic disease like intellectual disability, 64 00:03:05,970 --> 00:03:09,510 which is commonly associated with a genetic abnormality, 65 00:03:09,510 --> 00:03:13,770 as we've been talking about earlier in the semester. 66 00:03:13,770 --> 00:03:17,130 And this pediatric genetics, 67 00:03:17,130 --> 00:03:19,980 you know, there are some really specific considerations here 68 00:03:19,980 --> 00:03:22,530 because as you can appreciate, 69 00:03:22,530 --> 00:03:27,530 you want to maintain autonomy and decision making 70 00:03:28,290 --> 00:03:30,900 for a genetic test result for an individual. 71 00:03:30,900 --> 00:03:35,340 And in the pediatric setting, you know, it's for a child, 72 00:03:35,340 --> 00:03:38,790 and the child doesn't have the ability 73 00:03:38,790 --> 00:03:41,580 to make an informed decision 74 00:03:41,580 --> 00:03:43,110 at that point until they're an adult. 75 00:03:43,110 --> 00:03:47,280 So the goal is to really try 76 00:03:47,280 --> 00:03:51,690 to save that decision for the child to make 77 00:03:51,690 --> 00:03:54,270 when the child is of age to do that. 78 00:03:54,270 --> 00:03:57,840 The exceptions would be, and we'll talk about this shortly, 79 00:03:57,840 --> 00:04:00,180 but the exceptions will really be 80 00:04:00,180 --> 00:04:02,520 if we're testing for a condition 81 00:04:02,520 --> 00:04:05,710 that the child is going to potentially manifest 82 00:04:06,600 --> 00:04:09,000 during their pediatric stage, 83 00:04:09,000 --> 00:04:12,930 or we could do something to affect the potential progression 84 00:04:12,930 --> 00:04:15,270 of a disease that might manifest later 85 00:04:15,270 --> 00:04:18,840 by having some kind of intervention early on. 86 00:04:18,840 --> 00:04:23,070 Adult genetic testing is a different consideration 87 00:04:23,070 --> 00:04:24,480 after pediatric because again, 88 00:04:24,480 --> 00:04:27,870 now you have the consideration of autonomy 89 00:04:27,870 --> 00:04:30,720 and an individual can decide for his or herself 90 00:04:30,720 --> 00:04:31,920 whether or not they would want 91 00:04:31,920 --> 00:04:33,690 to have a genetic test result. 92 00:04:33,690 --> 00:04:35,790 And we've been talking about this 93 00:04:35,790 --> 00:04:37,410 on the discussion board as well, 94 00:04:37,410 --> 00:04:38,730 I think some great conversations 95 00:04:38,730 --> 00:04:41,550 and just thinking about what would you want to do. 96 00:04:41,550 --> 00:04:44,370 And each patient certainly has the right 97 00:04:44,370 --> 00:04:46,320 to consider that for his or herself, 98 00:04:46,320 --> 00:04:49,200 whether or not they want to know, what they want to know, 99 00:04:49,200 --> 00:04:51,090 when they want to know it. 100 00:04:51,090 --> 00:04:53,580 Because the difference between a genetic test result 101 00:04:53,580 --> 00:04:56,910 and say other kinds of lab results is 102 00:04:56,910 --> 00:05:00,120 that a genetic test result is for life. 103 00:05:00,120 --> 00:05:03,900 When you find out what your particular genetic makeup is 104 00:05:03,900 --> 00:05:05,640 for one gene or set of genes, 105 00:05:05,640 --> 00:05:07,380 or even in the future in your whole genome, 106 00:05:07,380 --> 00:05:08,970 that's not going to change. 107 00:05:08,970 --> 00:05:12,240 So once you know it, you can't really unknow it. 108 00:05:12,240 --> 00:05:14,910 So it's important to really consider it carefully 109 00:05:14,910 --> 00:05:17,883 and for the patient to make that decision for themselves. 110 00:05:19,980 --> 00:05:21,750 Geriatric genetic testing 111 00:05:21,750 --> 00:05:24,150 is actually becoming much more common, 112 00:05:24,150 --> 00:05:25,860 and it may provide useful information 113 00:05:25,860 --> 00:05:27,963 to the patient and their family. 114 00:05:28,920 --> 00:05:31,590 However, common age-related conditions like dementia 115 00:05:31,590 --> 00:05:33,960 are not typically linked with alleles included 116 00:05:33,960 --> 00:05:35,640 in most genetic tests. 117 00:05:35,640 --> 00:05:37,530 So you may have some genetic testing 118 00:05:37,530 --> 00:05:39,270 that is actually helpful 119 00:05:39,270 --> 00:05:44,270 in say, finding the right dose or the right drugs 120 00:05:44,580 --> 00:05:47,400 if there's pharmacogenetic information that's known. 121 00:05:47,400 --> 00:05:51,060 Pharmacogenetics basically just means assessing 122 00:05:51,060 --> 00:05:54,660 a specific set of genes that are typically involved 123 00:05:54,660 --> 00:05:58,740 in metabolism of a drug, of a set of drugs, 124 00:05:58,740 --> 00:06:02,940 and using that to infer how a patient will respond 125 00:06:02,940 --> 00:06:07,893 to a drug therapy and the dosage of a drug therapy. 126 00:06:10,323 --> 00:06:13,350 It's not available for most drugs certainly, 127 00:06:13,350 --> 00:06:14,820 but there are some 128 00:06:14,820 --> 00:06:18,870 that there is some good pharmacogenetic data available 129 00:06:18,870 --> 00:06:20,490 and some good tests that can be run 130 00:06:20,490 --> 00:06:23,730 to help determine ideal dosage, 131 00:06:23,730 --> 00:06:25,980 or the dosage and drug selection 132 00:06:25,980 --> 00:06:28,470 that would be likely to be the safest 133 00:06:28,470 --> 00:06:31,230 and more effective in that particular individual. 134 00:06:31,230 --> 00:06:34,470 And so that's being used in the geriatric population as well 135 00:06:34,470 --> 00:06:38,190 where there are certainly significant risks 136 00:06:38,190 --> 00:06:41,430 to the individual if they get the wrong drug 137 00:06:41,430 --> 00:06:42,633 or the wrong dose. 138 00:06:44,220 --> 00:06:45,660 So let's start at the beginning 139 00:06:45,660 --> 00:06:47,190 or actually before the beginning, 140 00:06:47,190 --> 00:06:49,440 preconception and prenatal testing. 141 00:06:49,440 --> 00:06:53,190 Preconception genetic counseling can be beneficial for those 142 00:06:53,190 --> 00:06:56,340 with a family history of a specific genetic disease 143 00:06:56,340 --> 00:06:58,260 or members of ethnicities or races 144 00:06:58,260 --> 00:07:00,570 with high risk of certain genetic diseases. 145 00:07:00,570 --> 00:07:04,110 We've spoken about the Ashkenazi Jewish population 146 00:07:04,110 --> 00:07:07,124 and that population in particular, 147 00:07:07,124 --> 00:07:09,600 there's a set of genetic diseases 148 00:07:09,600 --> 00:07:14,460 for which they typically have a higher carrier frequency 149 00:07:14,460 --> 00:07:16,080 than in the average population. 150 00:07:16,080 --> 00:07:20,970 And especially if you have both individuals in the couple 151 00:07:20,970 --> 00:07:22,290 that's considering having a child, 152 00:07:22,290 --> 00:07:27,060 if both of them are from the same race or ethnic group 153 00:07:27,060 --> 00:07:32,060 where you do have these higher frequencies of carriers, 154 00:07:32,880 --> 00:07:36,420 then it can be certainly advisable 155 00:07:36,420 --> 00:07:40,620 for that couple to seek genetic counseling 156 00:07:40,620 --> 00:07:43,320 just to better understand the risks 157 00:07:43,320 --> 00:07:47,433 and you know, what their options are moving forward. 158 00:07:48,450 --> 00:07:52,000 Preconception testing is usually for carrier status 159 00:07:53,130 --> 00:07:55,740 because most likely by the time 160 00:07:55,740 --> 00:07:58,200 you're undergoing preconception counseling, 161 00:07:58,200 --> 00:07:59,580 we're talking about adults, 162 00:07:59,580 --> 00:08:04,200 and if they wanted to have tested themselves 163 00:08:04,200 --> 00:08:06,060 for a genetic condition, they're concerned 164 00:08:06,060 --> 00:08:07,560 that they themselves will manifest, 165 00:08:07,560 --> 00:08:09,720 they would've already done it by now, most likely, 166 00:08:09,720 --> 00:08:12,150 not always, but most likely. 167 00:08:12,150 --> 00:08:14,730 But so it's more likely to test for carrier status 168 00:08:14,730 --> 00:08:17,040 because you're not going to be symptomatic 169 00:08:17,040 --> 00:08:18,210 and you wouldn't really know 170 00:08:18,210 --> 00:08:20,163 unless you had this genetic test done. 171 00:08:21,000 --> 00:08:24,660 Prenatal testing typically focuses on testing the fetus 172 00:08:24,660 --> 00:08:27,840 for genetic disease or chromosomal abnormality. 173 00:08:27,840 --> 00:08:31,050 And this could be testing for a specific genetic disease 174 00:08:31,050 --> 00:08:34,080 that's known to run in someone's family 175 00:08:34,080 --> 00:08:36,580 or that's more common in their ethnic group 176 00:08:37,530 --> 00:08:39,600 or those chromosomal abnormalities. 177 00:08:39,600 --> 00:08:42,333 And chromosomal abnormalities, as you remember, 178 00:08:44,066 --> 00:08:47,760 are actually typically a random event 179 00:08:47,760 --> 00:08:50,010 and unlikely to have been inherited, 180 00:08:50,010 --> 00:08:52,680 so unlikely to have run in the family, 181 00:08:52,680 --> 00:08:56,340 but most likely to have just happened rather spontaneously 182 00:08:56,340 --> 00:08:58,083 or as a random event. 183 00:09:00,090 --> 00:09:04,650 In women or couples where you've had many, 184 00:09:04,650 --> 00:09:07,920 say where there's been a higher incidence 185 00:09:07,920 --> 00:09:10,380 of spontaneous abortions, 186 00:09:10,380 --> 00:09:11,920 or if they have had a child 187 00:09:13,020 --> 00:09:16,023 who has had a chromosomal abnormality, 188 00:09:16,890 --> 00:09:19,920 it's probably beneficial for them 189 00:09:19,920 --> 00:09:21,930 to undergo genetic testing 190 00:09:21,930 --> 00:09:26,400 if that's something the couple wants to know. 191 00:09:26,400 --> 00:09:29,670 As with any tests, of course, 192 00:09:29,670 --> 00:09:32,080 what we're talking about here is 193 00:09:33,270 --> 00:09:38,270 that the individual or the family members involved 194 00:09:38,460 --> 00:09:42,240 are all well informed, that they make a decision based 195 00:09:42,240 --> 00:09:45,870 upon that information and knowing what they will do 196 00:09:45,870 --> 00:09:48,300 with that information when the test result comes back. 197 00:09:48,300 --> 00:09:50,430 Same thing for the healthcare providers as well, 198 00:09:50,430 --> 00:09:52,130 knowing what are you going to do 199 00:09:52,130 --> 00:09:54,120 if the result comes back positive or negative 200 00:09:54,120 --> 00:09:57,060 or inconclusive, and being informed 201 00:09:57,060 --> 00:09:58,953 before undergoing the test. 202 00:10:00,300 --> 00:10:02,130 Preconception results may inform 203 00:10:02,130 --> 00:10:04,290 or influence future reproductive decisions, 204 00:10:04,290 --> 00:10:06,630 while prenatal results may inform the decision 205 00:10:06,630 --> 00:10:09,300 to carry to term or help prepare the family 206 00:10:09,300 --> 00:10:11,280 for a child's future care. 207 00:10:11,280 --> 00:10:13,980 So again, when we're thinking about what are we going to do 208 00:10:13,980 --> 00:10:16,290 with this information, that's the part 209 00:10:16,290 --> 00:10:19,230 that needs to be filled in, if possible, 210 00:10:19,230 --> 00:10:22,620 with the information from the couple, 211 00:10:22,620 --> 00:10:24,910 the families, everybody involved 212 00:10:24,910 --> 00:10:28,500 to think through what are they going to do 213 00:10:28,500 --> 00:10:30,480 depending upon the results that come back. 214 00:10:30,480 --> 00:10:32,130 And it still might not be enough 215 00:10:32,130 --> 00:10:35,040 to fully prepare them when the results come back, 216 00:10:35,040 --> 00:10:37,440 but at least they're starting to think about it 217 00:10:37,440 --> 00:10:39,090 and they're making an informed decision 218 00:10:39,090 --> 00:10:41,973 as to whether or not they wish to pursue those tests. 219 00:10:43,020 --> 00:10:44,640 Preconception and prenatal testing 220 00:10:44,640 --> 00:10:46,290 can both significantly impact 221 00:10:46,290 --> 00:10:49,260 the patient's emotional wellbeing and relationships. 222 00:10:49,260 --> 00:10:52,710 And this is of course, critical to keep in mind. 223 00:10:52,710 --> 00:10:56,700 And as we've been talking about in the discussion boards, 224 00:10:56,700 --> 00:10:59,610 it really does kind of come down to a gut feeling 225 00:10:59,610 --> 00:11:02,550 of whether you do or do not want to know something. 226 00:11:02,550 --> 00:11:05,760 And this is the same for prenatal 227 00:11:05,760 --> 00:11:07,200 or even preconception testing. 228 00:11:07,200 --> 00:11:09,390 Some people just will not want to know, 229 00:11:09,390 --> 00:11:12,120 and it would be detrimental to their emotional wellbeing 230 00:11:12,120 --> 00:11:15,210 and potentially to their relationships if they do. 231 00:11:15,210 --> 00:11:19,170 So thinking through it, being very clear, especially going 232 00:11:19,170 --> 00:11:22,170 to see genetic counseling if at all possible, 233 00:11:22,170 --> 00:11:25,203 would be the best option. 234 00:11:27,240 --> 00:11:29,280 Alright, so we're talking about tests here, 235 00:11:29,280 --> 00:11:33,660 and I wanted to throw in a quick reminder if you've seen 236 00:11:33,660 --> 00:11:35,010 this before, hopefully you have, 237 00:11:35,010 --> 00:11:38,250 if not, the concept is relatively straightforward 238 00:11:38,250 --> 00:11:40,080 for our purposes here, 239 00:11:40,080 --> 00:11:44,460 about a diagnostic sensitivity versus specificity. 240 00:11:44,460 --> 00:11:46,650 So we're gonna be talking about testing, 241 00:11:46,650 --> 00:11:51,030 but there's primarily, you can think of two kinds broadly, 242 00:11:51,030 --> 00:11:52,470 two kinds of testing, 243 00:11:52,470 --> 00:11:54,990 one being more of a screen, 244 00:11:54,990 --> 00:11:59,040 which a screen would be looking at a large population 245 00:11:59,040 --> 00:12:01,890 and trying to identify individuals 246 00:12:01,890 --> 00:12:05,340 who are likely to have a disease or a condition 247 00:12:05,340 --> 00:12:07,980 out of the whole big population, 248 00:12:07,980 --> 00:12:12,420 versus a diagnostic test where this is very likely 249 00:12:12,420 --> 00:12:14,400 to be a much smaller population 250 00:12:14,400 --> 00:12:16,860 where there's already reason to believe 251 00:12:16,860 --> 00:12:18,630 someone might have a condition, 252 00:12:18,630 --> 00:12:20,610 there's a suspicion of one sort or another, 253 00:12:20,610 --> 00:12:22,950 whether it's they're demonstrating some kind 254 00:12:22,950 --> 00:12:26,430 of signs or symptoms or there's risk factors associated 255 00:12:26,430 --> 00:12:28,950 with them that would increase the chance 256 00:12:28,950 --> 00:12:30,330 that they would have this condition 257 00:12:30,330 --> 00:12:31,773 or develop this condition. 258 00:12:32,994 --> 00:12:35,220 So you want to keep that in mind. 259 00:12:35,220 --> 00:12:39,630 And those kinds of tests then are very likely 260 00:12:39,630 --> 00:12:43,230 to positively identify those 261 00:12:43,230 --> 00:12:45,870 who indeed do have the condition, 262 00:12:45,870 --> 00:12:47,250 who indeed do have the condition. 263 00:12:47,250 --> 00:12:49,680 So we're talking about sensitivity and specificity 264 00:12:49,680 --> 00:12:53,100 as measures that are reported out 265 00:12:53,100 --> 00:12:56,970 for different diagnostics and screens. 266 00:12:56,970 --> 00:12:58,380 Sensitivity, you can think of 267 00:12:58,380 --> 00:13:00,120 as a measure of a test's ability 268 00:13:00,120 --> 00:13:03,360 to identify those at risk for a condition. 269 00:13:03,360 --> 00:13:06,753 So high sensitivity would be best for screening, 270 00:13:07,950 --> 00:13:10,830 thinking of it as ruling out. 271 00:13:10,830 --> 00:13:15,830 So it's going to come back potentially with a group. 272 00:13:15,870 --> 00:13:16,703 So let's say we're starting 273 00:13:16,703 --> 00:13:20,370 with the whole population of the United States. 274 00:13:20,370 --> 00:13:23,400 Let's say there's 300, 275 00:13:23,400 --> 00:13:26,310 let's just say there's 300 million people in the US 276 00:13:26,310 --> 00:13:29,220 and we're screening every single one of them 277 00:13:29,220 --> 00:13:31,290 for a particular condition. 278 00:13:31,290 --> 00:13:34,530 And what comes back is that it comes back 279 00:13:34,530 --> 00:13:36,210 with 1% of the population. 280 00:13:36,210 --> 00:13:38,160 So 3 million people come back 281 00:13:38,160 --> 00:13:40,650 with a positive result on that screen. 282 00:13:40,650 --> 00:13:43,020 It doesn't mean all 3 million people 283 00:13:43,020 --> 00:13:45,720 have this condition we're screening for. 284 00:13:45,720 --> 00:13:47,290 What it does mean is 285 00:13:48,251 --> 00:13:51,060 that really virtually no one 286 00:13:51,060 --> 00:13:54,240 in the remaining 297 million people 287 00:13:54,240 --> 00:13:57,180 who got a negative result for the screen, 288 00:13:57,180 --> 00:14:00,360 virtually none of them are actually positive. 289 00:14:00,360 --> 00:14:03,690 But in our group that came back as testing positive, 290 00:14:03,690 --> 00:14:06,930 there's likely quite a few who are actually negative, 291 00:14:06,930 --> 00:14:10,230 but they received a positive result on the screen. 292 00:14:10,230 --> 00:14:11,100 Why is this? 293 00:14:11,100 --> 00:14:15,600 Well, we want to have the highest sensitivity for a screen 294 00:14:15,600 --> 00:14:17,310 because we don't wanna miss anybody. 295 00:14:17,310 --> 00:14:19,680 We want to first narrow our group down. 296 00:14:19,680 --> 00:14:21,930 Let's say now we're down to that 1% of the population. 297 00:14:21,930 --> 00:14:24,810 Okay, so now what can we do in that 1% of the population? 298 00:14:24,810 --> 00:14:27,060 Now we can check each of them, 299 00:14:27,060 --> 00:14:30,833 with one of these really high specificity tests, 300 00:14:33,120 --> 00:14:36,060 which is going to basically confirm 301 00:14:36,060 --> 00:14:39,900 or really give us a much more clear diagnosis 302 00:14:39,900 --> 00:14:42,720 that a person has a particular condition. 303 00:14:42,720 --> 00:14:46,380 So in a highly sensitive test, 304 00:14:46,380 --> 00:14:50,010 basically if you get a negative result, 305 00:14:50,010 --> 00:14:51,570 you can feel really confident 306 00:14:51,570 --> 00:14:53,640 that the person truly is negative, 307 00:14:53,640 --> 00:14:55,440 that they don't have this condition. 308 00:14:55,440 --> 00:14:57,150 And that's why we wanna use it for a screen. 309 00:14:57,150 --> 00:15:00,270 We're trying, we're casting, you know, casting a wide net 310 00:15:00,270 --> 00:15:01,860 across the whole population 311 00:15:01,860 --> 00:15:03,810 to make sure that we're not missing anybody 312 00:15:03,810 --> 00:15:05,010 who actually has the condition. 313 00:15:05,010 --> 00:15:06,780 And then if that comes back positive, 314 00:15:06,780 --> 00:15:08,770 there's an immediate reflex test 315 00:15:10,055 --> 00:15:14,700 for a highly specific, a test with high specificity 316 00:15:14,700 --> 00:15:16,290 to confirm the results. 317 00:15:16,290 --> 00:15:18,960 So this would give low false positives. 318 00:15:18,960 --> 00:15:20,910 So now we're gonna take that reduced population 319 00:15:20,910 --> 00:15:22,500 that came back as positive from the screen. 320 00:15:22,500 --> 00:15:25,500 We're gonna test all of them with a different kind of test 321 00:15:25,500 --> 00:15:27,780 that's going to have high specificity 322 00:15:27,780 --> 00:15:30,330 so that we can feel confident that every one of those 323 00:15:30,330 --> 00:15:33,600 that comes back is positive, truly is positive, 324 00:15:33,600 --> 00:15:35,730 truly is positive, okay? 325 00:15:35,730 --> 00:15:39,660 So oftentimes there's several tests 326 00:15:39,660 --> 00:15:40,910 that are grouped together 327 00:15:42,840 --> 00:15:46,440 to confirm that an individual has a particular condition, 328 00:15:46,440 --> 00:15:50,160 especially if it's something like a condition 329 00:15:50,160 --> 00:15:52,653 that we're testing for in the broad population. 330 00:15:54,060 --> 00:15:57,600 Okay, so hopefully that's pretty clear. 331 00:15:57,600 --> 00:16:01,590 You can think of a high sensitivity test as a rule-out test. 332 00:16:01,590 --> 00:16:06,590 So we're trying to, everybody who tests negative, 333 00:16:06,630 --> 00:16:09,600 you can rule yourself out as having that condition. 334 00:16:09,600 --> 00:16:12,160 And high specificity test is a rule-in condition. 335 00:16:12,160 --> 00:16:14,550 So if it comes back positive, you can feel certain 336 00:16:14,550 --> 00:16:17,520 that that person truly is positive. 337 00:16:17,520 --> 00:16:19,650 Ideally, I mean, sure, in a perfect world, 338 00:16:19,650 --> 00:16:20,760 we would want all tests 339 00:16:20,760 --> 00:16:24,030 to be both highly sensitive and highly specific. 340 00:16:24,030 --> 00:16:27,960 The reality is that's very challenging 341 00:16:27,960 --> 00:16:31,050 and certainly is a goal of all diagnostics makers, 342 00:16:31,050 --> 00:16:35,583 but not something that can always be achieved. 343 00:16:37,680 --> 00:16:41,040 Okay, so thinking about some of the risks and cautions 344 00:16:41,040 --> 00:16:43,740 in prenatal testing and screening, false positives, 345 00:16:43,740 --> 00:16:46,320 so this indicates the fetus has a genetic disease 346 00:16:46,320 --> 00:16:48,300 or disorder when that is not the case. 347 00:16:48,300 --> 00:16:50,910 And false negatives, so that would be indicating 348 00:16:50,910 --> 00:16:53,400 the fetus does not have a genetic condition or disorder 349 00:16:53,400 --> 00:16:55,230 that is actually present, 350 00:16:55,230 --> 00:16:57,810 can occur with any genetic test or screen 351 00:16:57,810 --> 00:17:01,020 and must be explained as a possibility to the patient. 352 00:17:01,020 --> 00:17:03,090 So even if something comes back 353 00:17:03,090 --> 00:17:04,770 and it's saying it's positive 354 00:17:04,770 --> 00:17:06,870 or it's a negative result, 355 00:17:06,870 --> 00:17:10,330 usually with every diagnostic, they report back 356 00:17:11,280 --> 00:17:12,840 some kind of an indicator 357 00:17:12,840 --> 00:17:16,050 of the false positive and false negative rate. 358 00:17:16,050 --> 00:17:19,530 And that could be used to help explain those risks 359 00:17:19,530 --> 00:17:23,430 to the patient that's receiving this information. 360 00:17:23,430 --> 00:17:25,740 So all screens that return a positive result 361 00:17:25,740 --> 00:17:28,170 must be followed up with other clinical diagnostics 362 00:17:28,170 --> 00:17:29,940 to confirm, as we talked about, 363 00:17:29,940 --> 00:17:31,500 not just another genetic test, 364 00:17:31,500 --> 00:17:34,770 but also there would any other kind of diagnostics 365 00:17:34,770 --> 00:17:37,170 that can be used to complement that, just to confirm 366 00:17:37,170 --> 00:17:40,230 that the positive result truly is positive. 367 00:17:40,230 --> 00:17:42,090 Some prenatal tests are invasive. 368 00:17:42,090 --> 00:17:44,490 So this is important to keep in mind. 369 00:17:44,490 --> 00:17:49,350 Amniocentesis and CVS in particular are. 370 00:17:49,350 --> 00:17:51,780 CVS in particular is quite invasive. 371 00:17:51,780 --> 00:17:56,780 And each of these types of procedures carries 372 00:17:56,820 --> 00:18:01,170 with it a risk of abortion that can happen, 373 00:18:01,170 --> 00:18:03,940 spontaneous abortion, miscarriage that can happen 374 00:18:05,220 --> 00:18:07,050 as a result of the test itself. 375 00:18:07,050 --> 00:18:10,470 And that risk may not be acceptable 376 00:18:10,470 --> 00:18:12,333 to the patient who's considering it. 377 00:18:14,550 --> 00:18:17,430 All right, cell-free fetal DNA testing. 378 00:18:17,430 --> 00:18:19,936 So if we're trying to move past 379 00:18:19,936 --> 00:18:23,850 the time when we're using amnio and CVS 380 00:18:23,850 --> 00:18:26,940 to test prenatal samples, 381 00:18:26,940 --> 00:18:28,920 we're moving to a time where we're trying to be 382 00:18:28,920 --> 00:18:30,990 as non-invasive as possible. 383 00:18:30,990 --> 00:18:34,023 And this is called non-invasive prenatal testing or NIPT. 384 00:18:34,860 --> 00:18:37,830 It's a promising approach to prenatal genetic testing, 385 00:18:37,830 --> 00:18:39,150 reducing risk to the mother 386 00:18:39,150 --> 00:18:40,710 and fetus from invasive procedures. 387 00:18:40,710 --> 00:18:42,810 And basically all it requires is 388 00:18:42,810 --> 00:18:45,000 to draw a blood sample from the mother 389 00:18:45,000 --> 00:18:48,870 and to sort out the fetal DNA from the mother's DNA. 390 00:18:48,870 --> 00:18:50,250 And it's really interesting, 391 00:18:50,250 --> 00:18:54,120 actually there's DNA 392 00:18:54,120 --> 00:18:57,420 that is basically sort of floating around 393 00:18:57,420 --> 00:19:01,860 in the amniotic fluid that then crosses the placenta 394 00:19:01,860 --> 00:19:03,300 and crosses into the mother, 395 00:19:03,300 --> 00:19:05,490 into the bloodstream of the mother. 396 00:19:05,490 --> 00:19:08,490 So there is some small, small amounts, 397 00:19:08,490 --> 00:19:10,500 very small amounts of fetal DNA. 398 00:19:10,500 --> 00:19:13,650 It's called cell-free because there aren't actually cells, 399 00:19:13,650 --> 00:19:16,020 whole cells from the fetus floating around, 400 00:19:16,020 --> 00:19:18,930 but it's DNA from the fetus, 401 00:19:18,930 --> 00:19:21,940 is again, small amount is floating around 402 00:19:22,800 --> 00:19:25,170 and circulating in the mother's blood. 403 00:19:25,170 --> 00:19:27,420 So if we take a blood draw from the mother, 404 00:19:27,420 --> 00:19:30,510 and using molecular techniques can actually separate 405 00:19:30,510 --> 00:19:33,330 out the maternal from the fetal DNA, 406 00:19:33,330 --> 00:19:35,970 then what you could do is test that fetal DNA 407 00:19:35,970 --> 00:19:39,750 and see you know, what conditions are present 408 00:19:39,750 --> 00:19:44,250 without ever having to invade into the uterus 409 00:19:44,250 --> 00:19:46,290 or take amniotic fluid 410 00:19:46,290 --> 00:19:48,840 or take a sample from the fetus itself, 411 00:19:48,840 --> 00:19:52,140 without any of those invasive procedures. 412 00:19:52,140 --> 00:19:54,870 Basically, you're just taking a blood draw. 413 00:19:54,870 --> 00:19:58,680 So this really is the future of testing. 414 00:19:58,680 --> 00:20:01,560 Obviously it relies upon technologies 415 00:20:01,560 --> 00:20:04,020 to be able to reliably separate fetal DNA 416 00:20:04,020 --> 00:20:05,760 from the maternal DNA. 417 00:20:05,760 --> 00:20:07,290 And that is a challenge, 418 00:20:07,290 --> 00:20:11,670 but that is absolutely the direction that testing is going. 419 00:20:11,670 --> 00:20:13,530 Newborn screening and genetic testing. 420 00:20:13,530 --> 00:20:16,950 So newborn screening is mandated by each state in the US. 421 00:20:16,950 --> 00:20:20,400 And the Department of Health for each of those states is 422 00:20:20,400 --> 00:20:23,340 in charge of determining which conditions 423 00:20:23,340 --> 00:20:26,820 they're testing for and how it's managed. 424 00:20:26,820 --> 00:20:28,350 In the state of Vermont, parents have the right 425 00:20:28,350 --> 00:20:30,180 to refuse screening for any reason. 426 00:20:30,180 --> 00:20:31,710 However, they have to state 427 00:20:31,710 --> 00:20:34,200 that they are refusing screening. 428 00:20:34,200 --> 00:20:39,180 Otherwise the newborn will be screened. 429 00:20:39,180 --> 00:20:41,760 So they have to actively request that it not happen. 430 00:20:41,760 --> 00:20:43,320 They're not asked. 431 00:20:43,320 --> 00:20:44,310 Babies born at home. 432 00:20:44,310 --> 00:20:45,750 And the reason for that is 433 00:20:45,750 --> 00:20:48,780 because it's viewed as a public health issue. 434 00:20:48,780 --> 00:20:53,070 Because if you can catch these conditions early on, 435 00:20:53,070 --> 00:20:56,220 these conditions which often manifest very early, 436 00:20:56,220 --> 00:20:57,720 very soon after birth, 437 00:20:57,720 --> 00:21:01,230 they're commonly metabolic conditions that only manifest 438 00:21:01,230 --> 00:21:03,693 once the child starts feeding in many cases. 439 00:21:05,010 --> 00:21:07,980 Or they're conditions where early intervention 440 00:21:07,980 --> 00:21:10,530 would make a world of difference to the child. 441 00:21:10,530 --> 00:21:13,350 So these are biochemical tests 442 00:21:13,350 --> 00:21:14,580 that are done on the blood. 443 00:21:14,580 --> 00:21:19,580 You can see that in the picture, in the top right corner, 444 00:21:19,800 --> 00:21:21,330 it's what's called a heel prick test. 445 00:21:21,330 --> 00:21:23,430 So the newborn's heel is pricked, 446 00:21:23,430 --> 00:21:27,270 and the blood is collected on a card. 447 00:21:27,270 --> 00:21:30,330 And that card is sent off to the lab and testing is done. 448 00:21:30,330 --> 00:21:32,970 It's usually biochemical type of testing on the blood 449 00:21:32,970 --> 00:21:35,300 to see if there's any abnormalities 450 00:21:35,300 --> 00:21:39,230 in the typical blood biochemistry that might be associated 451 00:21:39,230 --> 00:21:41,340 with certain conditions. 452 00:21:41,340 --> 00:21:44,490 Many of those conditions are genetic conditions, 453 00:21:44,490 --> 00:21:47,880 but this is not a genetic test per se. 454 00:21:47,880 --> 00:21:52,880 It's not actually doing any sequencing here on the screen. 455 00:21:53,040 --> 00:21:55,680 They're just looking for biochemical abnormalities. 456 00:21:55,680 --> 00:21:57,360 And so this is a screen, remember, 457 00:21:57,360 --> 00:22:00,240 so we're looking at the whole population we're screening. 458 00:22:00,240 --> 00:22:03,540 And so when it comes back as positive, 459 00:22:03,540 --> 00:22:07,470 it may or may not actually be positive. 460 00:22:07,470 --> 00:22:10,230 If it comes back as negative, you can feel really confident 461 00:22:10,230 --> 00:22:13,590 that in fact the child does not have that condition. 462 00:22:13,590 --> 00:22:15,900 But if it comes back as positive, 463 00:22:15,900 --> 00:22:18,060 there's a reflex test that's done 464 00:22:18,060 --> 00:22:22,290 with a more highly specific diagnostic for that condition, 465 00:22:22,290 --> 00:22:25,350 usually actual genetic sequencing that would be done 466 00:22:25,350 --> 00:22:27,780 if it's a genetic condition to confirm 467 00:22:27,780 --> 00:22:29,970 that in fact the child does have a genetic condition. 468 00:22:29,970 --> 00:22:33,810 So even if a screen comes back as positive for something, 469 00:22:33,810 --> 00:22:37,740 doesn't necessarily mean it's going to be positive 470 00:22:37,740 --> 00:22:41,610 by the time, you know, all the diagnostics come back in. 471 00:22:41,610 --> 00:22:45,150 Babies born at home, and this happens a lot in Vermont, 472 00:22:45,150 --> 00:22:48,900 babies born at home have newborn screening if requested 473 00:22:48,900 --> 00:22:50,973 by the parents in an office visit. 474 00:22:52,140 --> 00:22:54,720 And Vermont, so in the state of Vermont, 475 00:22:54,720 --> 00:22:57,090 we have 29 conditions in newborn screening. 476 00:22:57,090 --> 00:22:59,253 And you can find a list of those. 477 00:23:00,360 --> 00:23:03,450 There's a link to the Department of Health site 478 00:23:03,450 --> 00:23:06,480 in the reading folder, online resources for this week 479 00:23:06,480 --> 00:23:09,270 if you're interested in checking out the conditions 480 00:23:09,270 --> 00:23:11,470 that are tested for in the state of Vermont. 481 00:23:12,930 --> 00:23:16,290 So how do they decide which conditions go onto a list? 482 00:23:16,290 --> 00:23:18,450 And as I said, each state decides separately. 483 00:23:18,450 --> 00:23:19,350 There are some conditions 484 00:23:19,350 --> 00:23:21,510 that are tested for in every state 485 00:23:21,510 --> 00:23:24,300 but there are other conditions that are not. 486 00:23:24,300 --> 00:23:29,300 And in general, the way screening is determined, 487 00:23:29,550 --> 00:23:32,760 whether or not they're going to screen for a condition is 488 00:23:32,760 --> 00:23:34,740 they use these criteria 489 00:23:34,740 --> 00:23:38,700 that were developed in the '60s actually from a group, 490 00:23:38,700 --> 00:23:41,250 from the World Health Organization, 491 00:23:41,250 --> 00:23:44,520 Wilson and Jungner screening criteria. 492 00:23:44,520 --> 00:23:47,790 And these would include assessing the condition 493 00:23:47,790 --> 00:23:51,480 for whether or not it is a serious health problem, 494 00:23:51,480 --> 00:23:54,540 whether there's accepted treatment available, 495 00:23:54,540 --> 00:23:58,980 if it can be diagnosed, if there're recognizable latent 496 00:23:58,980 --> 00:24:01,860 or early onset symptoms that can be addressed. 497 00:24:01,860 --> 00:24:04,950 There's a suitable test acceptable to the population. 498 00:24:04,950 --> 00:24:07,260 So all of these are really necessary. 499 00:24:07,260 --> 00:24:08,400 If there isn't a suitable test 500 00:24:08,400 --> 00:24:10,320 and if it doesn't work in the population, 501 00:24:10,320 --> 00:24:13,260 it's not going to be something we can include in the screen. 502 00:24:13,260 --> 00:24:15,780 It's a well understood natural history for the condition. 503 00:24:15,780 --> 00:24:18,510 So it's not something so rare 504 00:24:18,510 --> 00:24:21,780 that we don't even understand how the disease works. 505 00:24:21,780 --> 00:24:24,150 There's an agreed policy who is treated. 506 00:24:24,150 --> 00:24:26,880 So if it comes back positive, who would be treated? 507 00:24:26,880 --> 00:24:29,190 Cost of testing and treatment is balanced 508 00:24:29,190 --> 00:24:33,090 to the cost of treating the condition 509 00:24:33,090 --> 00:24:36,450 or testing for the condition individually, 510 00:24:36,450 --> 00:24:39,570 and that there's a continuing process of reassessment 511 00:24:39,570 --> 00:24:42,810 as new data, new treatment becomes available. 512 00:24:42,810 --> 00:24:46,560 So this is one way in which organizations 513 00:24:46,560 --> 00:24:48,780 and departments of health will assess 514 00:24:48,780 --> 00:24:50,670 and decide which conditions are included 515 00:24:50,670 --> 00:24:52,023 in newborn screening. 516 00:24:53,700 --> 00:24:55,080 So the future of newborn screening. 517 00:24:55,080 --> 00:24:57,630 With whole genome sequencing becoming readily available 518 00:24:57,630 --> 00:24:59,370 and cost-effective, the possibility 519 00:24:59,370 --> 00:25:01,590 of newborn genome screening becomes, 520 00:25:01,590 --> 00:25:04,320 or newborn genome sequencing rather becomes real. 521 00:25:04,320 --> 00:25:07,620 So this is an interesting idea, right? 522 00:25:07,620 --> 00:25:10,950 So instead of just testing for one thing at a time, 523 00:25:10,950 --> 00:25:14,340 doing one genetic test at a time, 524 00:25:14,340 --> 00:25:16,200 let's just sequence the entire genome 525 00:25:16,200 --> 00:25:17,750 right from the moment of birth. 526 00:25:18,810 --> 00:25:20,070 Well, it's an interesting idea 527 00:25:20,070 --> 00:25:23,250 and for some it may seem like, well, 528 00:25:23,250 --> 00:25:24,507 this is perfectly logical, let's do that. 529 00:25:24,507 --> 00:25:27,660 And for others it may make you feel queasy 530 00:25:27,660 --> 00:25:28,980 to think about that 531 00:25:28,980 --> 00:25:32,880 as you know, we've talked about autonomy 532 00:25:32,880 --> 00:25:37,110 and the the right to make a decision for yourself 533 00:25:37,110 --> 00:25:39,570 as to what information you do and do not want to know. 534 00:25:39,570 --> 00:25:42,180 Privacy becomes a real question, 535 00:25:42,180 --> 00:25:44,160 and finding out information 536 00:25:44,160 --> 00:25:46,170 about which we can really do nothing 537 00:25:46,170 --> 00:25:49,350 and whether that's valuable or not. 538 00:25:49,350 --> 00:25:52,260 So there are lots of questions to consider here, 539 00:25:52,260 --> 00:25:55,980 but there are a few health centers that are piloting this, 540 00:25:55,980 --> 00:25:58,653 large health centers that are piloting this. 541 00:25:59,490 --> 00:26:02,880 And it's, you know, it's tough to say right now whether 542 00:26:02,880 --> 00:26:05,250 that's the direction we're going to end up going, 543 00:26:05,250 --> 00:26:08,640 but certainly we don't have enough information 544 00:26:08,640 --> 00:26:11,400 to be able to interpret whole genomes, 545 00:26:11,400 --> 00:26:14,670 to know what to do with all of that information yet. 546 00:26:14,670 --> 00:26:19,670 So I don't see it on the five-year horizon certainly, 547 00:26:19,950 --> 00:26:23,010 but looking out beyond that 10, 15, 20 years from now, 548 00:26:23,010 --> 00:26:25,170 it's absolutely a possibility. 549 00:26:25,170 --> 00:26:29,520 And I believe we would need to have a significant amount 550 00:26:29,520 --> 00:26:34,520 of policy in place and clear clinical guidelines, 551 00:26:35,010 --> 00:26:39,780 clear privacy measures to set up to address those concerns 552 00:26:39,780 --> 00:26:42,120 before we would move forward with this. 553 00:26:42,120 --> 00:26:43,720 That would certainly be my hope. 554 00:26:45,030 --> 00:26:48,810 So let's hope that that's how it works 555 00:26:48,810 --> 00:26:51,123 if it does move in that direction. 556 00:26:52,200 --> 00:26:55,500 So now let's move up into a little bit older timeframe. 557 00:26:55,500 --> 00:26:57,750 Now we're talking about pediatric genetics. 558 00:26:57,750 --> 00:26:59,910 So children presenting with symptoms consistent 559 00:26:59,910 --> 00:27:02,610 with a genetic disease may, with parental consent, 560 00:27:02,610 --> 00:27:05,730 undergo genetic testing to aid in diagnosis. 561 00:27:05,730 --> 00:27:09,480 So if a child is complaining, has symptoms, issues, 562 00:27:09,480 --> 00:27:11,490 again, we mentioned intellectual disability 563 00:27:11,490 --> 00:27:14,500 as a common red flag of a genetic disease 564 00:27:15,630 --> 00:27:18,720 which often shows up in pediatric population 565 00:27:18,720 --> 00:27:20,730 as opposed to any earlier than that. 566 00:27:20,730 --> 00:27:25,730 So this would certainly raise the possibility 567 00:27:25,740 --> 00:27:27,690 for genetic testing to aid in diagnosis, 568 00:27:27,690 --> 00:27:32,010 which would potentially lead to better informed treatment. 569 00:27:32,010 --> 00:27:34,020 The American Academy of Pediatrics recommends 570 00:27:34,020 --> 00:27:36,570 the principle factor in making the decision 571 00:27:36,570 --> 00:27:39,510 for genetic testing is whether it is in the best interest 572 00:27:39,510 --> 00:27:41,670 of the child, of the child. 573 00:27:41,670 --> 00:27:42,503 And I think of course, 574 00:27:42,503 --> 00:27:45,060 that's always the best way to go. 575 00:27:45,060 --> 00:27:47,550 Predictive genetic testing is only recommended 576 00:27:47,550 --> 00:27:49,110 for those diseases with onset 577 00:27:49,110 --> 00:27:51,690 or possible intervention during childhood 578 00:27:51,690 --> 00:27:52,920 with parental consent 579 00:27:52,920 --> 00:27:55,440 and when possible with child consent 580 00:27:55,440 --> 00:27:57,000 to best inform the child. 581 00:27:57,000 --> 00:28:00,780 And you know, if they're say in their teenage years, 582 00:28:00,780 --> 00:28:03,870 it may be possible for them to make an informed decision 583 00:28:03,870 --> 00:28:06,300 or to help in that informed decision. 584 00:28:06,300 --> 00:28:08,310 Adult onset predictive disease testing 585 00:28:08,310 --> 00:28:09,980 is not generally deemed to be 586 00:28:09,980 --> 00:28:11,550 in the best interest of the child, 587 00:28:11,550 --> 00:28:14,220 again, to try to retain autonomy 588 00:28:14,220 --> 00:28:15,930 so that the child can make that decision 589 00:28:15,930 --> 00:28:17,910 for his or herself in the future. 590 00:28:17,910 --> 00:28:19,320 And certainly carrier status 591 00:28:19,320 --> 00:28:23,010 is almost universally not pursued in children 592 00:28:23,010 --> 00:28:24,000 as it's only relevant 593 00:28:24,000 --> 00:28:26,310 for family planning for the individual. 594 00:28:26,310 --> 00:28:28,980 So let that individual make that decision for themselves 595 00:28:28,980 --> 00:28:31,113 when they're of age to be able to do that. 596 00:28:33,210 --> 00:28:34,980 Okay, let's move on up to adults. 597 00:28:34,980 --> 00:28:36,930 So in adults, we have genetic diseases 598 00:28:36,930 --> 00:28:39,777 with adult onset may be tested for in the adult population, 599 00:28:39,777 --> 00:28:41,910 and those who have a family history 600 00:28:41,910 --> 00:28:43,710 and have decided to do so. 601 00:28:43,710 --> 00:28:46,530 Often they're sent to genetic counseling 602 00:28:46,530 --> 00:28:48,570 to best understand their risks 603 00:28:48,570 --> 00:28:51,960 and to talk through what are the possible options 604 00:28:51,960 --> 00:28:53,580 for testing, what are the results, 605 00:28:53,580 --> 00:28:55,350 what are the implications, 606 00:28:55,350 --> 00:28:58,380 and just to make sure everyone's well informed 607 00:28:58,380 --> 00:28:59,910 before they make a decision. 608 00:28:59,910 --> 00:29:01,590 Huntington's disease, which we've talked about 609 00:29:01,590 --> 00:29:03,390 a decent amount in this class, 610 00:29:03,390 --> 00:29:05,760 is an autosomal dominant neurodegenerative disease. 611 00:29:05,760 --> 00:29:08,130 And patient may choose to be tested for 612 00:29:08,130 --> 00:29:09,540 if one of his or her parents 613 00:29:09,540 --> 00:29:11,970 or grandparents had Huntington's disease. 614 00:29:11,970 --> 00:29:15,480 But as we talked about last week, I believe, 615 00:29:15,480 --> 00:29:20,130 you know, if a grandparent has Huntington's disease, 616 00:29:20,130 --> 00:29:24,330 and let's say an individual, that individual wants 617 00:29:24,330 --> 00:29:28,200 to be tested, but their parent, 618 00:29:28,200 --> 00:29:30,900 let's say it was their maternal grandfather 619 00:29:30,900 --> 00:29:32,790 who had Huntington's disease, 620 00:29:32,790 --> 00:29:35,100 and then their mother does not want to know 621 00:29:35,100 --> 00:29:37,770 whether or not she has Huntington's disease, 622 00:29:37,770 --> 00:29:39,300 but the child comes of age 623 00:29:39,300 --> 00:29:41,940 and decides that he wants to know. 624 00:29:41,940 --> 00:29:43,440 So he undergoes genetic testing 625 00:29:43,440 --> 00:29:46,110 and finds out he is positive for Huntington's disease. 626 00:29:46,110 --> 00:29:47,880 Then he knows his mother 627 00:29:47,880 --> 00:29:50,220 also has Huntington's disease despite the fact 628 00:29:50,220 --> 00:29:54,780 that she did not agree or decide to have that test done. 629 00:29:54,780 --> 00:29:56,280 So there's a lot of complicating factors, 630 00:29:56,280 --> 00:29:58,380 but you know, at the same time, we can't restrict the right 631 00:29:58,380 --> 00:30:01,830 of that individual to have his genetic testing done. 632 00:30:01,830 --> 00:30:04,950 Once he's an adult, he can decide that for himself. 633 00:30:04,950 --> 00:30:09,240 So there's a balance that has to be sought 634 00:30:09,240 --> 00:30:12,570 whenever we're talking about these ethical situations 635 00:30:12,570 --> 00:30:14,910 and trying to maintain autonomy 636 00:30:14,910 --> 00:30:18,360 and informed consent for everyone involved. 637 00:30:18,360 --> 00:30:22,020 But it's almost impossible in every situation to do that. 638 00:30:22,020 --> 00:30:25,380 So cancer predisposition testing may be recommended 639 00:30:25,380 --> 00:30:27,150 for those with a family history of cancer 640 00:30:27,150 --> 00:30:29,400 or red flags of heritable cancer risk. 641 00:30:29,400 --> 00:30:34,320 And again, they'd likely be sent to genetic counseling 642 00:30:34,320 --> 00:30:39,270 and take a really complete family history, pedigree analysis 643 00:30:39,270 --> 00:30:42,450 and assess what genetic tests are available 644 00:30:42,450 --> 00:30:45,753 for the inheritable forms of cancer. 645 00:30:47,070 --> 00:30:48,990 Carrier status may be tested 646 00:30:48,990 --> 00:30:51,540 in those planning to have children. 647 00:30:51,540 --> 00:30:55,320 So that way it could help to inform their decisions 648 00:30:55,320 --> 00:30:57,840 about whether or not they want 649 00:30:57,840 --> 00:31:00,600 to pursue having children biologically 650 00:31:00,600 --> 00:31:03,990 or if, you know, it may inform the kind of testing 651 00:31:03,990 --> 00:31:06,843 they would want to have done in prenatal testing, 652 00:31:07,830 --> 00:31:11,040 or it can also just help them to better prepare 653 00:31:11,040 --> 00:31:12,840 for the possibility of having a child 654 00:31:12,840 --> 00:31:14,673 with certain conditions. 655 00:31:16,350 --> 00:31:19,080 Okay, moving to the geriatric population, 656 00:31:19,080 --> 00:31:22,140 Alzheimer's disease, age-related macular degeneration 657 00:31:22,140 --> 00:31:24,330 and cancer are common age-related diseases 658 00:31:24,330 --> 00:31:26,160 with a demonstrated genetic component. 659 00:31:26,160 --> 00:31:28,950 So there certainly is rationale for testing 660 00:31:28,950 --> 00:31:31,650 for these conditions in geriatric population. 661 00:31:31,650 --> 00:31:33,840 There's also a rationale for testing. 662 00:31:33,840 --> 00:31:37,290 Let's say if someone in the geriatric population develops 663 00:31:37,290 --> 00:31:40,110 age-related macular degeneration, 664 00:31:40,110 --> 00:31:44,340 there may be reason to have them tested, 665 00:31:44,340 --> 00:31:45,990 undergo genetic testing. 666 00:31:45,990 --> 00:31:47,970 Even though that won't inform 667 00:31:47,970 --> 00:31:49,953 that treatment for that person, 668 00:31:51,060 --> 00:31:54,990 it could help to inform any of their relatives 669 00:31:54,990 --> 00:31:58,530 about their potential risk if it's genetic. 670 00:31:58,530 --> 00:32:01,440 So say a an elderly patient comes in 671 00:32:01,440 --> 00:32:03,450 with macular degeneration 672 00:32:03,450 --> 00:32:06,420 and the thought is, okay, we could do genetic testing 673 00:32:06,420 --> 00:32:10,080 to see if the reason for or part of the contribution 674 00:32:10,080 --> 00:32:12,210 for this macular degeneration is genetic. 675 00:32:12,210 --> 00:32:13,650 It comes back positive. 676 00:32:13,650 --> 00:32:17,970 Then that individual can inform their relatives 677 00:32:17,970 --> 00:32:20,160 of their potential risk of it as well. 678 00:32:20,160 --> 00:32:22,050 And they may undergo genetic testing 679 00:32:22,050 --> 00:32:27,050 to see if they also have the alleles for those diseases. 680 00:32:28,320 --> 00:32:31,770 So it may not be directly helpful 681 00:32:31,770 --> 00:32:34,740 for the health of the person who's getting the test, 682 00:32:34,740 --> 00:32:36,960 but it can help inform the health 683 00:32:36,960 --> 00:32:41,583 and potential future testing of other folks in their family. 684 00:32:43,110 --> 00:32:45,780 Alzheimer's disease, genetic testing is restricted 685 00:32:45,780 --> 00:32:48,330 to select alleles demonstrated to contribute 686 00:32:48,330 --> 00:32:50,190 to early onset Alzheimer's disease, 687 00:32:50,190 --> 00:32:54,750 not late onset Alzheimer's disease or late onset dementia. 688 00:32:54,750 --> 00:32:58,830 So that's really more for developing Alzheimer's disease 689 00:32:58,830 --> 00:33:00,993 before the age of 65. 690 00:33:02,190 --> 00:33:05,310 There is a pretty substantial amount of data 691 00:33:05,310 --> 00:33:07,680 to support there's a genetic component there. 692 00:33:07,680 --> 00:33:10,560 And again, if someone develops Alzheimer's disease, 693 00:33:10,560 --> 00:33:15,000 say 58, 60 years old, it may not help them 694 00:33:15,000 --> 00:33:16,830 to have genetic testing directly, 695 00:33:16,830 --> 00:33:19,890 but it could help to inform their family members 696 00:33:19,890 --> 00:33:23,550 of their potential risk for Alzheimer's disease 697 00:33:23,550 --> 00:33:26,463 from an increased genetic risk, that is. 698 00:33:28,260 --> 00:33:32,640 All right, so some of the results that can come back, 699 00:33:32,640 --> 00:33:34,680 you might just think, well, it's gonna be positive 700 00:33:34,680 --> 00:33:35,640 or it's gonna be negative. 701 00:33:35,640 --> 00:33:38,490 They're gonna say, yes you do, or no, you do not have it. 702 00:33:38,490 --> 00:33:43,050 Unfortunately, there is a third possibility for a result. 703 00:33:43,050 --> 00:33:47,430 And this is not uncommon, not uncommon at all 704 00:33:47,430 --> 00:33:50,700 to get this result, which is the VUS, 705 00:33:50,700 --> 00:33:53,100 variant of unknown significance. 706 00:33:53,100 --> 00:33:54,090 What is that? 707 00:33:54,090 --> 00:33:59,090 Well, it basically means we don't know what the sequence, 708 00:33:59,370 --> 00:34:02,430 what that that person's sequence is going to indicate 709 00:34:02,430 --> 00:34:04,560 in terms of disease or not. 710 00:34:04,560 --> 00:34:08,830 So it means that they sequenced someone's allele 711 00:34:10,500 --> 00:34:12,570 of a gene that's associated 712 00:34:12,570 --> 00:34:15,480 with a particular disease or condition, 713 00:34:15,480 --> 00:34:18,270 and it comes back and the sequence is not wild-type. 714 00:34:18,270 --> 00:34:20,400 It's not one of the typical wild-type sequences 715 00:34:20,400 --> 00:34:24,450 that we commonly see in the population of healthy folks, 716 00:34:24,450 --> 00:34:26,850 but it's also not one of the alleles known 717 00:34:26,850 --> 00:34:28,653 to cause this disease. 718 00:34:29,910 --> 00:34:32,040 So what do you do with that information? 719 00:34:32,040 --> 00:34:34,950 It's a change in the sequence 720 00:34:34,950 --> 00:34:36,630 and it would have to be a change in the sequence 721 00:34:36,630 --> 00:34:40,830 that would result in an amino acid substitution, 722 00:34:40,830 --> 00:34:42,060 so it would either have to be a missense 723 00:34:42,060 --> 00:34:43,860 or nonsense mutation, 724 00:34:43,860 --> 00:34:47,460 so not just a silent mutation because we have tons of those 725 00:34:47,460 --> 00:34:49,290 and they don't matter effectively 726 00:34:49,290 --> 00:34:52,170 because it doesn't affect the amino acid 727 00:34:52,170 --> 00:34:54,660 that's coded for, right? 728 00:34:54,660 --> 00:34:56,610 So that's not really what we're talking about here. 729 00:34:56,610 --> 00:35:00,030 We're talking about a missense or nonsense mutation. 730 00:35:00,030 --> 00:35:03,090 Usually a missense mutation is what we're seeing. 731 00:35:03,090 --> 00:35:05,190 And it's unclear as to whether 732 00:35:05,190 --> 00:35:06,930 or not that could result in the disease. 733 00:35:06,930 --> 00:35:08,070 So then you would get a result 734 00:35:08,070 --> 00:35:10,650 of it's a variant of unknown significance. 735 00:35:10,650 --> 00:35:12,720 We can't tell right now. 736 00:35:12,720 --> 00:35:14,700 And it can be really confusing and frustrating 737 00:35:14,700 --> 00:35:16,950 for a patient who's anticipating coming into the office 738 00:35:16,950 --> 00:35:18,240 and getting an answer. 739 00:35:18,240 --> 00:35:20,700 They probably paid, you know, a decent amount of money 740 00:35:20,700 --> 00:35:24,000 for the test, had to wait six, eight weeks 741 00:35:24,000 --> 00:35:24,833 to get the results. 742 00:35:24,833 --> 00:35:26,040 And they go in to hear 743 00:35:26,040 --> 00:35:29,340 and they're expecting to hear, yes you do, no you don't. 744 00:35:29,340 --> 00:35:32,190 Well, the third option is that it could be we don't know. 745 00:35:33,360 --> 00:35:36,540 And the only thing we can really say to this is 746 00:35:36,540 --> 00:35:39,660 that future research may link that variant 747 00:35:39,660 --> 00:35:40,920 to a specific risk, 748 00:35:40,920 --> 00:35:43,020 but as of today, there's no clear way 749 00:35:43,020 --> 00:35:44,430 to interpret those results. 750 00:35:44,430 --> 00:35:47,790 It could be that it does increase the risk 751 00:35:47,790 --> 00:35:48,623 for this condition 752 00:35:48,623 --> 00:35:52,380 or it could just be a perfectly finely functioning protein 753 00:35:52,380 --> 00:35:53,640 with no real issues 754 00:35:53,640 --> 00:35:56,550 and it's not going to result in the disease at all. 755 00:35:56,550 --> 00:35:57,960 And it's just something, a sequence 756 00:35:57,960 --> 00:36:01,080 that we just haven't come across yet until now, 757 00:36:01,080 --> 00:36:03,060 but we don't really have a better way 758 00:36:03,060 --> 00:36:04,080 to interpret it than that. 759 00:36:04,080 --> 00:36:05,910 And it can be really frustrating as you can imagine, 760 00:36:05,910 --> 00:36:07,510 for patients to get that result. 761 00:36:10,170 --> 00:36:11,640 So is this a good idea? 762 00:36:11,640 --> 00:36:15,030 Reported outcomes in patients following genetic testing. 763 00:36:15,030 --> 00:36:17,820 So BRCA 1/2, there's been reported 764 00:36:17,820 --> 00:36:19,870 there's a temporary stress relieved 765 00:36:22,320 --> 00:36:27,060 beep, temporary stress relieved long-term, 766 00:36:27,060 --> 00:36:29,640 increased surveillance and general improvement 767 00:36:29,640 --> 00:36:32,340 to health long-term in most patients. 768 00:36:32,340 --> 00:36:34,950 So while it might result in the temporary stress, 769 00:36:34,950 --> 00:36:37,290 that is relieved in the longer term, 770 00:36:37,290 --> 00:36:41,700 and that in general does result in better surveillance, 771 00:36:41,700 --> 00:36:44,263 general improvement to long-term health in most patients 772 00:36:44,263 --> 00:36:46,710 who come back with a positive result 773 00:36:46,710 --> 00:36:48,660 for the BRCA 1/2 test. 774 00:36:48,660 --> 00:36:51,510 Alzheimer's disease, neutral to slightly positive impact 775 00:36:51,510 --> 00:36:53,370 on psychological health long-term 776 00:36:53,370 --> 00:36:55,920 for those who decide that they want to have the test 777 00:36:55,920 --> 00:36:57,810 and it comes back positive. 778 00:36:57,810 --> 00:36:59,670 For Huntington's disease, short-term 779 00:36:59,670 --> 00:37:03,000 in the seven to 10 days post results impacts, 780 00:37:03,000 --> 00:37:07,053 worsens depressant scores for those who test positive. 781 00:37:07,950 --> 00:37:10,500 But depression scores improve long-term 782 00:37:10,500 --> 00:37:13,200 for those who test positive and negative. 783 00:37:13,200 --> 00:37:15,900 So if you take the population as a whole, 784 00:37:15,900 --> 00:37:17,460 that's how it averages out. 785 00:37:17,460 --> 00:37:19,980 I will just caution to say, you know, 786 00:37:19,980 --> 00:37:21,870 whenever we're talking about the psychological 787 00:37:21,870 --> 00:37:24,990 or psychosocial impact of anything, 788 00:37:24,990 --> 00:37:27,120 of course each individual has to be considered 789 00:37:27,120 --> 00:37:29,970 in their own context, in their own lives, 790 00:37:29,970 --> 00:37:31,380 in their own wishes. 791 00:37:31,380 --> 00:37:33,270 Because while this, again, this is taken 792 00:37:33,270 --> 00:37:37,230 as an average of the population, that doesn't mean 793 00:37:37,230 --> 00:37:40,590 that for each person it's going to turn out this way. 794 00:37:40,590 --> 00:37:45,590 So, you know, as always, their wishes, their interests, 795 00:37:45,630 --> 00:37:48,330 their understanding of their own situation is 796 00:37:48,330 --> 00:37:51,300 what's most important to consider. 797 00:37:51,300 --> 00:37:53,580 But if we do take the population as a whole, 798 00:37:53,580 --> 00:37:55,290 what we see generally is 799 00:37:55,290 --> 00:37:58,710 that even if the result comes back positive, 800 00:37:58,710 --> 00:38:02,220 people are at least no worse off psychologically 801 00:38:02,220 --> 00:38:04,620 and potentially slightly better off psychologically 802 00:38:04,620 --> 00:38:07,680 and may be more proactive in their health. 803 00:38:07,680 --> 00:38:09,630 Especially when it's something like BRCA 1/2, 804 00:38:09,630 --> 00:38:12,210 where they can actually do something about it, 805 00:38:12,210 --> 00:38:16,150 like going and getting more surveillance, breast exams 806 00:38:18,294 --> 00:38:20,760 and really taking more of an active role 807 00:38:20,760 --> 00:38:23,313 in preventing breast cancer and ovarian cancer. 808 00:38:26,340 --> 00:38:28,950 Okay, so again, considering all possible outcomes 809 00:38:28,950 --> 00:38:30,840 from a test, negative, positive 810 00:38:30,840 --> 00:38:32,820 and that third one, the unknown, 811 00:38:32,820 --> 00:38:35,730 and their impact on the approach to patient's care, 812 00:38:35,730 --> 00:38:37,920 so what are you going to do differently? 813 00:38:37,920 --> 00:38:39,510 What are other healthcare providers going 814 00:38:39,510 --> 00:38:41,340 to do differently with that information? 815 00:38:41,340 --> 00:38:43,620 Positive or negative lifestyle changes, 816 00:38:43,620 --> 00:38:45,990 patient's psychological and emotional welfare. 817 00:38:45,990 --> 00:38:48,810 Where are they now? Where might this lead them? 818 00:38:48,810 --> 00:38:50,790 Patients', family and/or social group 819 00:38:50,790 --> 00:38:52,680 and their support structure, 820 00:38:52,680 --> 00:38:55,410 their understanding of their own health and wellbeing, 821 00:38:55,410 --> 00:38:58,060 and the patient's healthcare coverage and employment, 822 00:38:58,980 --> 00:39:00,980 these are all important to keep in mind. 823 00:39:02,040 --> 00:39:04,680 So the question really comes down 824 00:39:04,680 --> 00:39:07,350 to what will you, the patient's healthcare team 825 00:39:07,350 --> 00:39:09,690 and/or the patient do differently in response 826 00:39:09,690 --> 00:39:13,470 to each of all possible test result outcomes? 827 00:39:13,470 --> 00:39:16,530 And this is commonly what a genetic counselor will walk 828 00:39:16,530 --> 00:39:19,350 through with a patient and their family members, 829 00:39:19,350 --> 00:39:21,570 and just thinking through what are we gonna do 830 00:39:21,570 --> 00:39:22,403 if it's positive? 831 00:39:22,403 --> 00:39:23,250 What if it's negative? 832 00:39:23,250 --> 00:39:24,540 What if it's inconclusive? 833 00:39:24,540 --> 00:39:26,940 And make sure they've thought through everything 834 00:39:26,940 --> 00:39:30,393 before they make a decision on pursuing a test. 835 00:39:31,860 --> 00:39:33,990 So in summary, all stages of life, 836 00:39:33,990 --> 00:39:36,390 genetic testing requires careful consideration 837 00:39:36,390 --> 00:39:38,400 of all possible implications of results 838 00:39:38,400 --> 00:39:40,080 for the patient and their family. 839 00:39:40,080 --> 00:39:42,030 Decisions and actions that may be informed 840 00:39:42,030 --> 00:39:44,400 or influenced by genetic test results differ depending 841 00:39:44,400 --> 00:39:45,780 on the life stage, 842 00:39:45,780 --> 00:39:48,060 and advances in genetic testing technologies 843 00:39:48,060 --> 00:39:50,250 interpretation of results must be approached 844 00:39:50,250 --> 00:39:52,200 with great care for the ethical, social 845 00:39:52,200 --> 00:39:54,870 and legal implications these results can have 846 00:39:54,870 --> 00:39:57,513 on the patient as a whole person. 847 00:39:58,530 --> 00:40:00,960 Okay, well that wraps it up here. 848 00:40:00,960 --> 00:40:02,880 And in the next week, 849 00:40:02,880 --> 00:40:05,613 so once we're wrapped up this module, 850 00:40:08,007 --> 00:40:09,090 we're going to start diving 851 00:40:09,090 --> 00:40:12,930 into some more advanced clinical topics related to genetics 852 00:40:12,930 --> 00:40:15,270 and genomics in these emerging fields, 853 00:40:15,270 --> 00:40:18,270 and give you a taste for a variety 854 00:40:18,270 --> 00:40:21,333 of different areas more specifically. 855 00:40:22,230 --> 00:40:24,090 And we're going to start that off next week 856 00:40:24,090 --> 00:40:26,130 with immunogenetics. 857 00:40:26,130 --> 00:40:29,280 Well, thank you very much for listening to this lecture, 858 00:40:29,280 --> 00:40:31,380 and I look forward to talking with you 859 00:40:31,380 --> 00:40:32,490 on the discussion board. 860 00:40:32,490 --> 00:40:33,513 Take care. Bye.