Mixed-methods evaluation of how 100,000 Genomes Project participants experienced receiving positive additional findings (PAFs) for cancer or familial hypercholesterolaemia and no additional findings (NAFs), with implications for clinical return pathways and patient support.
0:00Welcome to Base by Base, the paper cast that brings genomics to you wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. So imagine taking your car to the mechanic because the air conditioning is broken.
0:13Right, something simple. Yeah, exactly. You leave it there. The mechanic fixes the AC, but then walks out to the waiting room, you know, wipes his hands on a towel and says, by the way, while I was under the hood, I notice your brake lines are completely chewed through.
0:27Oh, wow. Yeah, that's a shock. Right. I mean, you didn't ask them to check the brakes. You were just hot, but knowing that information just saved your life. Which is great, but also terrifying. Totally.
0:38Now, imagine that scenario, but instead of your car, it's your body. And instead of a mechanic, it's a geneticist. You take a genetic test to find the cause of a specific ongoing health issue. Like a rare disease or something.
0:52Yeah, maybe you're looking for answers about a rare disease that has been impacting you or, you know, your child for years. But when the results come back, they reveal something entirely unexpected. Something else entirely.
1:03Exactly. A hidden genetic risk for a completely different life-threatening edition you had absolutely no idea was looking in your DNA. Out of nowhere. Out of nowhere. Yeah. Or on the flip side, you get a letter saying, no extra risks are found, and you mistakenly believe your DNA is entirely flawlessly healthy, like a sort of biological get out of jail free card.
1:27Yeah, which is a huge misconception because as genomic sequencing becomes a routine part of healthcare. We're suddenly faced with this, um, this really profound psychological challenge. How to deliver the news.
1:38Right. How do we deliver these secondary findings to patients? I mean, catching a disease before it starts is the ultimate goal of medicine, obviously. But dropping that kind of heavy, unexpected information on someone out of the blue, it carries a massive risk of causing, you know, unnecessary trauma.
1:55It's a lot to process. It really is. The medical community is basically racing to figure out how to handle the emotional fallout of our own technological success. Before we dig into how this is actually playing out in the clinics, though.
2:07We need to pause and celebrate the people doing the work on the ground. Today, we celebrate the work of the NHS North Thames Genomic Laboratory hub, Great Ormond Street Hospital, and the extensive network of clinical genetics teams across England, who have advanced our understanding of patient experiences in genomic medicine.
2:27Yeah, and we really have to acknowledge that gathering this kind of highly personal, highly sensitive data across so many different clinics and hospitals. It's an incredible logistical feat. can't even imagine the paperwork.
2:39Oh, it's massive. We are talking about tracking the emotional states of 1000s of people over years. It is really the only way we learn how to build a healthcare system that treats the human mind, not just the human genome.
2:53Okay, let's unpack this. We are looking at data that comes out of the 100,000 genomes project. For those who might not know the history. This was a massive initiative in England. A really groundbreaking one, yeah.
3:03It was a hybrid model, right? Part research part, clinical care. The initiative offered whole genome sequencing to around 85,000 patients and their relatives who were dealing with either rare diseases or cancer.
3:14Right, and the primary goal there was to find the main cause of their specific current illness. But then they added this extra layer. Yeah, participants were asked if they also wanted to receive what the project called additional findings or AFs.
3:27And what do the patients say? Well, over 90% of the participants said yes. They consented to have the researchers actively look for secondary genetic risks. Wow, 90%. That's huge. It is. Specifically, they were looking at 13 genes linked to cancer.
3:43So things like BRCA one and 2 and Lynch syndrome, and also 3 genes linked to familial hypercholesterolemia. Which is FH, right? The cholesterol one. Exactly. It's a genetic condition that causes dangerously high cholesterol.
3:56Now, I am a bit confused by that parameter. If you're sequencing the entire human genome, like all 3 billion base pairs. Why are you only reporting back on 16 specific genes? It's a really good question.
4:08I mean, if I give you my DNA, shouldn't you tell me about every single disease you find, why keep the rest a secret? So there is a vital line drawn in genomic medicine around the concept of actionability.
4:21Actionability. Yeah. The project purposely only looked for conditions where a medical intervention actually exists. Oh I see. Because if a sequencing algorithm finds a genetic variant that guarantees a patient will develop, say, a devastating neurodegenerative disease in 20 years, but we currently have absolutely no cure.
4:41No treatment? Nothing. Right. No preventative measures for that disease. Handing that information over doesn't help the patient. It simply acts as a psychological weight. Just decades of severe anxiety.
4:53Exactly, without offering a medical solution. So the parameters are strictly limited to things you can actually fight. Preventative surgery for cancer risk or, you know, targeted medication for cholesterol.
5:04Like mechanic analogy. He only tells you about the brakes if he actually has the parts to replace them. That's a great way to put it. Yeah. That makes total sense. And this matters to you, the listener, regardless of where you live in the world.
5:16As genome sequencing extands globally and becomes, you know, incredibly cheap and accessible. 10000s of people are going to be asked this exact same question. Do you want to know your secondary genetic risks?
5:27Right. Understanding how these early participants reacted when they receive these results provides a crucial roadmap? We're looking at a preview of what your routine annual physical might look like in the very near future.
5:40It really is the future of medicine. And to figure out how patients were actually feeling about all this. The research team couldn't just look at medical charts. Right. You can't see anxiety on an x-ray.
5:51Exactly. So they deployed a convergent mixed methods design, which is basically a dual approach. First, they sent out detailed cross-sectional surveys to participants who received a positive additional finding, or PAF.
6:03A PAF, okay. What were the numbers on that? They got 146 surveys back from PAF patients. About 63% of those were for cancer risks, and 37% for FH. Got it. And then they did interviews. Yeah. Rather than just crunching the survey numbers.
6:19They sat down for in-depth qualitative interviews. They spoke at length with 35 patients who, you know, had the rug pulled out from under them with a PAF. Wow, those must have been heavy conversations.
6:31They were, and equally importantly, they talked to 29 people who got a NAFNO additional findings. Basically a clean bill of health on these secondary findings to see how they interpreted that news. Okay, but instead of using convoluted academic jargon.
6:46Let's talk about what they were actually measuring. Because how do you measure existential dread. You can't just ask someone to rate their panic on a scale of one to five. No, you can't. They utilize specific, establish psychological tools designed to measure the emotional fallout of medical news.
7:01Well, they use the decisional regret scale or DRS, and the multidimensional impact of cancer risk assessment, which we call my cower. My Karai, okay. Yeah, they didn't just ask, are you sad? They broke the psychological impact down.
7:15They measured uncertainty. Like, how unpredictable does the patient feel their future is now? That makes sense. They measured distress. Are they losing sleep, experiencing intrusive thoughts, and they measure decisional regret.
7:28Looking back, do they wish they had never checked the box consenting to know this information in the 1st place? Well, wait. I have to play the skeptic here for a 2nd regarding the panic and the shock. Okay, go for it.
7:40These people consented to this testing when they joined the project, right? They physically checked a box on a form saying, told me if I have a cancer gene. Yes, they did. So why would it be a shock? They literally asked for it.
7:53You have to consider the timeline and the cognitive load of a patient in crisis. The gap between that initial consent conversation and a busy hospital office and the moment they actually receive these secondary results was often several years.
8:06Yeah, and remember, when they signed the forms, they were deeply focused on their primary illness. They were trying to find out why their toddler was having seizures or, you know, they were in the middle of their own chemotherapy.
8:18Oh man. So the secondary stuff was just an afterthought. Exactly. Fast forward 3 or 4 years. They have completely forgotten the fine print of what they consented to. The letter or the phone call arrives entirely out of the blue.
8:32It creates a unique psychological pressure cooker because they are suddenly thrust into a new medical crisis. They just weren't emotionally preparing for. You sign a massive stack of paperwork. Years go by, and then a letter arrives on a random Tuesday saying you have a high risk for a completely different disease.
8:51Yeah, exactly that. Let's look at the actual outcomes, though, because the data isn't all doom and gloom, right? The overall utility of this program was incredibly positive. It was. Despite the initial shock of the news, the clinical support mechanisms generally worked.
9:0782% of the surveyed patients felt that the clinician who delivered the news successfully lessened their worries. That's great statistic. Yeah, older patients in particular were highly likely to report feeling reassured by their clinical teams.
9:20And patients didn't just sit on this information either, did they? No, not at all. 87% said the result would actively influence their health management moving forward. They were booking the extra screenings, consulting with specialists, making lifestyle changes.
9:33Which is the whole point, and a massive 90% shared the results of their families. That is the entire mechanical purpose of genetic screening, right? Alerting relatives who might carry the same mutation so they can get tested before symptoms appear.
9:47Precisely, but what's fascinating here is the contrast in how different genetic results were received. We really have to look at the divide between the cancer findings and the familial hypercholesterolemia finding.
9:59They hit different. Completely different. The human brain processes the threat of those 2 diseases in totally different ways. I mean, the quotes from the cancer patients in the data are incredibly heavy.
10:10You really feel the weight of the realization. Oh, absolutely. These patients describe feeling like a, quote, ticking time bomb. One participant stated, my brain stopped after the BRCA 2 bit. They were just stunned, overwhelmed, highly anxious.
10:25And that was especially severe if they didn't have any family history of cancer to prepare them for the possibility. Right. And you mentioned the Mayancerria data backs this up. It does. The cancer PFs resulted in significantly higher overall distress scores.
10:40We saw a mean score of 30.99 for cancer compared to a mean of just 24.44 for the FH group. Wow, that's a noticeable gap. Yeah, because the biology explains the psychology here. A gene like BRCA one or BRCA 2 is a tumor suppressor gene.
10:58Its job is to repair damaged DNA. When you have a mutation there, your cells lose their primary mechanism for fixing genetic errors. So they just compound over time, leading to cancer. Exactly. And patients understand this on a visceral level.
11:12They know their body's defenses are compromised. And that distress extended far beyond their own bodies. Selling family members. Yeah, it was fraught with profound guilt. Male participants who discovered they had a BRCA one mutation which heavily impacts female breast and ovarian cancer risk, were shocked not really for their own health, but because they immediately realized they might have passed the gene to their daughters.
11:32Oh, wow. It adds this incredible layer of parental guilt and anxiety to the diagnosis. And then you contrast that intense panic with the patients who found out they have a genetic risk for FH. These are people discovering they have a genetic butation that causes dangerously high cholesterol, putting them at major risk for early heart attacks.
11:52Right. Yet none of them describe feeling distressed in the same way. No, for the FH group, the news rarely landed as a total surprise. Because high cholesterol is incredibly visible in family histories.
12:03Everyone knows someone in their family with heart issues. Exactly. Someone in the family usually has a history of heart issues or takes cholesterol medication. The threat feels familiar. One patient described getting the FH news as a get up and go feeling.
12:17Get up and go. That's almost positive. Yeah, they saw it as highly manageable. Familial hypercholesterolemia is essentially a mechanical issue. The liver struggles to recycle LDL cholesterol from the blood.
12:29So what's the intervention? It's clear. You change your diet, you take a daily statin medication, and you get your blood levels checked. The path forward is medicalized in a way that feels routine and controllable.
12:41Whereas cancer prevention. Cancer prevention often involves major prophylactic surgeries like mastectomies or intense anxiety inducing screening regimens that constantly remind you of the threat. That perfectly explains why a cancer letter causes a breakdown, while a cholesterol letter just prompts a trip to the pharmacy.
13:00Exactly. But what about the regret factor? You mentioned the decisional regret scale earlier. If I get a letter out of the blue, telling me my cellular repair mechanisms are broken, and I'm a ticking time bomb, I might deeply regret checking that consent box 5 years ago.
13:15Did people wish they had stayed in the dark? You'd think so, but the measurement of decisional regret provided some of the most encouraging data in the entire study. Really? Yeah, overall regret across the entire group was remarkably low.
13:27The median score was just a 5 out of 100. A 5 out of 100. That's practically zero. Right. And when researchers dug into the roughly 17% of people who initially scored in the high regret category, the long form interviews revealed something really profound.
13:42That high regret was an acute temporary reaction to the shock. As time passed, and as they worked with genetic counselors to create a concrete action plan, the regret faded. Ah, so once they had a plan, the fear went down.
13:56Exactly. Once the unpredictable threat was translated into a scheduled series of screenings and preventative steps, they realized that as terrifying as the information was, possessing it gave them power over their own survival.
14:09So the panic is real, but it's transient, assuming the healthcare system steps in with the right support. Correct. But we have to talk about the vast majority of people in this project. Over 80,000 individuals received a no additional findings letter.
14:22They got the enough result. What happens to the psychology of a person who is told their genome is clear of these secondary risks? Well, here we encounter what we can call the NAF paradox. For most of those 80,000 people, The letter brought a massive wave of relief.
14:36Sure no bad news. But the interviews revealed severe, potentially dangerous misunderstandings regarding basic genetic health literacy. Some patients mistakenly assumed that because this specific screening came back negative, they were magically cleared of all genetic diseases.
14:54Oh, no. thought their DNA was perfect. Yes. And that is absolutely not what the test means. It simply means they do not carry pathogenic variants in those specific 16 genes. They could still have mutations in 1000s of other genes that the project wasn't looking at.
15:11Right. The mechanic said the brake lines look good, but the engine could still explode tomorrow. Exactly. People were walking around with a completely false sense of biological invincibility. Yes, which is dangerous.
15:21And there was another massive misunderstanding in this group too, wasn't there? Some people were actually devastated by the negative result. Yeah, and you really have to put yourself in the shoes of a patient who originally joined the 100,000 genomes project to find an answer for an undiagnosed, rare disease.
15:35Right. They've spent years desperate for a primary diagnosis. Exactly. So when they received the NF letter stating we found nothing, some of them confused this secondary screening with the search for their primary diagnosis.
15:48Oh, that's awful. They thought this letter meant the doctors had officially given up on finding out what was originally wrong with them. One patient stated, I will always be disappointed until I know what's wrong with me.
15:59They felt abandoned by the medical system. Yes, because the communication wasn't clear enough about which part of their genome was being reported on? That is heartbreaking. They're holding a letter that is supposed to be good news about cancer.
16:12And they are crying because they think nobody's looking for the cause of their child's seizures anymore. It's tragic. It just highlights how incredibly difficult the communication of complex science really is.
16:23So what are the actual implications here for how hospitals operate? Because the clinical world is moving toward this concept of genome 1st care. Right. And if we connect this to the bigger picture, genome 1st care relies on the idea that we uncover the genetic risk before the patient ever shows a single physical symptom.
16:44We intercept the disease before it begins. Which sounds great in theory. It does, but this study highlights a critical logistics failure and how we currently handle the delivery of that care. The fact that these results arrived years after the initial consent proves that a fire and forget consent model is just broken.
17:01We need robust ongoing contact. Absolutely. When a health system drops heavy genetic news on a patient out of nowhere, there have to be immediate support pathways already active. You cannot mail a letter saying you have a high risk of cancer, and then schedule an informational appointment for a month later.
17:18The psychological buffer needs to be immediate. It also means we cannot treat all genetic findings as if they carry the same emotional weight. No, definitely not. The data clearly shows that a cancer finding requires a vastly different clinical pathway than a cholesterol finding.
17:34If someone gets an FH result, a phone call from a nurse and a prescription for a statin might be completely sufficient. It usually is. But if someone gets a BRCA finding, they need immediate follow-up counseling.
17:46They need time to process the shock. They need psychological support on how to navigate the guilt of talking to their children about it. Yes, we must tailor the clinical approach to the specific mechanism of the disease.
17:57And furthermore, the healthcare system absolutely cannot ignore the patients who receive a no findings result. Right, the NF education gap. Mailing a simple, all clear letter is not enough. There needs to be an educational mechanism, perhaps a dedicated digital portal or a hotline they can call to ensure these patients do not walk away with a false sense of invincibility.
18:19Education and context are just as vital for the negative results as they are for the positive ones. Okay, I do have to question the universality of this data, though. When you look at who actually filled out these surveys and sat down for these long interviews, is this sample truly representative of the general population?
18:36That's a very fair question. Like, what does this mean for the average person who doesn't fit the demographic profile of the patients in this specific study? The researchers are highly transparent about the limitations of their sample in the paper.
18:49The participants in the study were self-selected. Meaning they chose to respond to the survey and volunteer for the interviews. And self-selection often skews data, right? Oh, heavily. Yeah. It skews toward individuals who already possess strong feelings or high anxiety about a topic, but more critically, the sample was incredibly homogeneous.
19:09It was roughly 89% white. 89% white. Okay. Yeah. And the participants were highly educated. with 53% holding a university degree or higher, plus they were entirely English speaking, as the survey wasn't offered in other languages.
19:23Well, sure, if you have a high level of formal education, and English use your 1st language, you're going to have a much easier time navigating a complex multi-page medical letter than someone who doesn't.
19:34Exactly. You have the vocabulary to understand what a pathogenic variant even is. Moving forward, as we integrate genomic sequencing into global healthcare. These clinical communication pathways absolutely must be tested across far more diverse populations.
19:50To ensure equity and genomic care. Yes. Building a cutting edge genomic healthcare system that only successfully communicates with highly educated English-speaking patients is a failure of public health.
20:02We have to design communication strategies that translate across different languages, varied cultural backgrounds and all levels of health literacy. We've covered a massive amount of ground here today, from the biological mechanics of a ticking time bomb to the hidden dangers of feeling genetically invincible.
20:17Bring it all home for us. What is the ultimate takeaway from all this data? Well, returning secondary genomic findings is highly valued by patients and drives proactive, lifesaving healthcare decisions, but the psychological weight of the news varies drastically by the specific disease.
20:33To successfully integrate genomics into routine care, health systems must move beyond a one-size fits all approach and offer deeply tailored condition-specific psychological support and education. It really makes you wonder about that mechanic checking the brakes of your own biology.
20:47What does this mean for the future of your own routine healthcare? If a simple blood test that your next annual checkup could hand you a definitive printed list of your ultimate genetic vulnerabilities, would you truly want to read the entire list?
21:00Or is there a quiet piece in not knowing? This episode was based on an open access article under the CCBY 4.0 license. You can find a direct link to the paper and the license in our episode description.
21:13If you enjoyed this, follow or subscribe in your podcast app and leave a 5 star rating. If you'd like to support our work, use the donation link in the description. Now stay with us for an original track created, especially for this episode, and inspired by the article you've just heard about.
21:28Thanks for listening and join us next time as we explore more science, base by base.
