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Epidemiology and the Hidden Denominator
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You know, usually when we talk about a medical diagnosis, there's this expectation of like absolute precision. It feels like engineering.
SPEAKER_00Oh, for sure. Very black and white.
SPEAKER_01Right. You break your arm, the x-ray shows that jagged white line on a black background, and the doctor just points to the screen and says, There it is. That's the problem.
SPEAKER_00Yeah, it's binary. You are either broken or you are intact. I mean, we find a lot of comfort in things that are visible, strictly categorized, and just neatly contained in a folder.
SPEAKER_01But then you step into the world of epidemiology and bleeding disorders, and suddenly that X-ray machine is well, it's essentially broken. We're looking at a diagnostic landscape that is incredibly murky.
SPEAKER_00Oh, murky is the perfect word for it.
SPEAKER_01Welcome to the deep dive. Today we are exploring this really fascinating paper by William Ayrd on von Willebrand disease and something called the hidden denominator.
SPEAKER_00Which is a great concept.
SPEAKER_01It really is. So for those of you who might not know, von Willebrand disease, or VWD, is widely recognized in the medical community as the most common inherited bleeding disorder. But right out of the gate, there is this massive glaring discrepancy in the numbers that, you know, it stops you in your tracks.
SPEAKER_00Right. The statistics are wild.
SPEAKER_01Exactly. Because population studies, when they look really broadly, they suggest that about 1% of all people have this disease. But if you look at actual clinics, the doctors are only seeing about one in a thousand cases with actual symptoms.
SPEAKER_00Yeah. And when you see a gap that large, I mean one in a hundred versus one in a thousand, you start to realize epidemiology isn't just about counting diseases. Right. The numbers are trying to tell us a much deeper story about who becomes visible in our health systems and who just stays completely hidden.
SPEAKER_01Okay, let's unpack this. How can a disease be simultaneously everywhere and nowhere?
SPEAKER_00It's a paradox, honestly.
SPEAKER_01Right. And if you are listening to this right now, you might be thinking, you know, I'm not a hematologist. I don't even know what Von Willebrand factor is. Why does this matter to me?
SPEAKER_00Which is a totally fair question.
SPEAKER_01It is. But understanding how medical prevalence is essentially just a story like a story that gets heavily filtered through human biases, clinical definitions, and shifting biology, it will completely change how you view medical statistics, news headlines, and honestly, even your own health records.
SPEAKER_00Absolutely. Because to understand those missing people, we first have to understand how we define the people we actually do count. The ones we can see. Right. In epidemiology, that counted group is called the numerator. And the fundamental issue with von Willebrand disease is that the numerator is highly unstable.
SPEAKER_01Wait, unstable how?
SPEAKER_00Well, it shifts depending entirely on the definition the medical community just decides to use on any given day.
SPEAKER_01I want to pause there because that sounds completely counterintuitive. The disease itself, like what is physically happening inside a human body, that doesn't change.
SPEAKER_00No, the biology doesn't change.
SPEAKER_01But you're saying our boundary for what we call a disease does change.
SPEAKER_00Exactly. Let's look at the biology first, just to ground this. In VWD, doctors are measuring von Willebrand factor, or VWF, in the blood.
SPEAKER_01Okay.
SPEAKER_00You can think of VWF as a specialized protein glue. When you get a cut, these proteins unfurl in your bloodstream like tiny nets, and they catch platelets to form a clot and stop the bleeding. Makes sense. But here is the critical factual core. VWF levels are continuous biological variables in the human population. There is no natural biological cliff separating a normal level from a disease level.
SPEAKER_01I was actually trying to wrap my head around this continuous variable idea earlier, and it feels a lot like a speed limit on a highway. Oh, well, like a yeah, like the road itself is continuous, and the speed the cars are traveling is a continuous spectrum. But the state just paints a line on a metal sign and says 65 miles per hour is the boundary between a law-abiding driver and a speeder.
SPEAKER_00Right. It's an artificial line on a natural spectrum.
SPEAKER_01Exactly. But what if the state suddenly changed the speed limit down to 55? Suddenly, thousands of drivers who haven't changed their behavior at all, who are driving the exact same way they were yesterday, are now technically speeders. The reality on the ground didn't change, just the arbitrary boundary we drew.
SPEAKER_00That analogy captures the dilemma perfectly. Because in the world of VWF testing, that speed limit change is happening right now.
SPEAKER_01Really? Where?
SPEAKER_00Specifically in what hematologists call the gray zone. That is the range between 30 and 50 international units per deciliter of this clotting protein.
SPEAKER_01Okay, so that 30 to 50 range is the battleground.
SPEAKER_00Oh, the debate over what to call people in this range is incredibly intense. Take the 2021 diagnostic guidelines they were released by a coalition of major hematology organizations.
SPEAKER_01What did they do?
SPEAKER_00They decided to classify patients who have abnormal bleeding and VWF levels anywhere below 50 as having type 1 VWD.
SPEAKER_01Wait, why lower the threshold? Are they just, you know, try to find more sick people?
SPEAKER_00Well, their goal was actually highly pragmatic and very patient-focused. They wanted to improve access to care for symptomatic people.
SPEAKER_01Oh, I see. Because of insurance.
SPEAKER_00Exactly. In many healthcare systems, if you don't have an official coded diagnosis, insurance simply won't cover the specialized treatment and you don't get help. So they moved the boundary to capture more people who genuinely needed assistance.
SPEAKER_01But moving a boundary like that has to have side effects, right? Because I know older frameworks and the more recent 2024 British Society for Hematology Guidelines, they are pushing back pretty hard on that 2021 definition.
SPEAKER_00They are. They urge extreme caution. Those groups prefer to label that 30 to 50 range as simply low VWF rather than giving it a full disease diagnosis.
SPEAKER_01Right, because of the label. Exactly.
SPEAKER_00Just like your speed limit analogy, that single definitional shift suddenly slaps thousands of people with a chronic disease label. They worry deeply about the consequences of over-medicalizing a biological gray zone.
SPEAKER_01That makes sense.
SPEAKER_00Yeah, because in that specific range, the link between the protein level in the blood and the actual risk of a major bleed is just much weaker.
SPEAKER_01This highlights such a crucial takeaway for anyone reading medical stats or, you know, panicking over a headline. Commonness does not imply triviality, but rarity does not imply severity.
SPEAKER_00That is a great way to put it.
SPEAKER_01The frequency of a disease and the actual day-to-day burden of that disease on a person's life, they are related, but they are absolutely not the same thing.
SPEAKER_00And the denominator problem complicates this even further.
SPEAKER_01Oh, right. The denominator. Let's get into that.
SPEAKER_00Because if the numerator, the people we actually count, is just this shifting debated boundary, we have to turn our attention to the denominator. That is the overall population we bothered to look at in the first place.
SPEAKER_01Because every fraction needs a bottom number. If the denominator is unstable, the whole 1% statistic we mentioned earlier completely falls apart. Like who exactly are we not seeing?
SPEAKER_00If we connect this to the bigger picture, VWD epidemiology basically functions like a set of nested Russian dolls.
SPEAKER_01Oh, interesting.
SPEAKER_00Yeah. So the biggest outermost doll represents everyone on earth who has the genetic coding for low VWF.
SPEAKER_01Okay. The huge group.
SPEAKER_00Right. Open that doll, and inside is a smaller one. These are people with the genetics who actually develop noticeable bleeding symptoms.
SPEAKER_01Shrinking already.
SPEAKER_00Open that one, and you find an even smaller doll people whose symptoms are severe enough or recognized enough to actually lead to medical testing.
SPEAKER_01Wow. Okay.
SPEAKER_00Inside that doll are the people who actually receive an official diagnosis based on whatever the guidelines of the day are. And finally, the tiniest doll in the very center represents the people who end up registered in a health system database or national registry.
SPEAKER_01So every single time you open a doll, the population shrinks dramatically.
SPEAKER_00Exactly.
SPEAKER_01But that shrinking isn't random. Like people don't just randomly get a highly specialized blood coagulation test on a Tuesday. They get tested because someone, somewhere, thought to ask a question.
SPEAKER_00And that question almost always arises from a clinical trigger.
SPEAKER_01Like what?
SPEAKER_00A dental extraction that just won't stop oozing, a tonsilectomy, childbirth, or heavy menstrual bleeding. Without a trigger that prompts a doctor to run a panel, you remain forever in that hidden denominator.
SPEAKER_01You just go about your life.
SPEAKER_00Right. You have the biological possibility of the disease circulating in your veins, but you remain epidemiologically quiet.
SPEAKER_01Here's where it gets really interesting, especially regarding who gets triggered to be tested, because at a genetic level, VWD is autosomal.
SPEAKER_00Meaning it affects males and females equally.
SPEAKER_01Right. Biologically, it is a strict one-to-one ratio. However, women face massive tests to their body's clotting system that men simply don't.
SPEAKER_00Oh, absolutely.
SPEAKER_01We are talking about heavy menstrual bleeding, postpartum bleeding, miscarriages, invasive gynecologic procedures.
SPEAKER_00Those events demand a tremendous amount of work from the hemostatic system. If there is a weakness in the clotting proteins, those are the moments it should become glaringly obvious.
SPEAKER_01So here's my pushback then. If women have these glaringly obvious recurring clinical triggers built into their biology, shouldn't they be drastically overrepresented in the diagnosed population?
SPEAKER_00You would think so.
SPEAKER_01I mean, shouldn't a disease that affects bleeding make itself hypervisible in women compared to men?
SPEAKER_00You would absolutely think so. But this brings us to a really tragic duality in both medicine and culture. These symptoms do bring women to medical attention all the time.
SPEAKER_01Right, they go to the doctor.
SPEAKER_00They do. Women go to doctors complaining of debilitating heavy periods. But society, and historically the medical field itself, often normalizes, minimizes, or stigmatizes reproductive bleeding. So instead of a doctor saying, Let's order a specialized blood coagulation test to check your von Willebrand factor, the bleeding is just brushed off.
SPEAKER_01Just totally dismissed.
SPEAKER_00Yeah. It's labeled as a normal part of being a woman, or it's blamed purely on hormonal fluctuations or gynecologic issues.
SPEAKER_01Yeah.
SPEAKER_00The systemic failure is that her blood is never tested for an underlying bleeding disorder.
SPEAKER_01Let me get this straight. She is simultaneously more likely to have symptoms that require a doctor and vastly more likely to have those symptoms ignored by the system when she gets there.
SPEAKER_00Exactly.
SPEAKER_01So she stays in the hidden denominator, not because her biology is hiding the disease, but because of our cultural and clinical blind spots.
SPEAKER_00And we see this systemic blind spot on a massive global scale as well.
SPEAKER_01How so?
SPEAKER_00If you look at world registries, the reported prevalence of VWD varies wildly depending on a nation's income classification.
SPEAKER_01Oh, sure, that makes sense.
SPEAKER_00In lower resource areas, clinics are often dealing with triage for immediately life-threatening conditions. So they usually only document the exceedingly rare, highly severe version of this disease, which is known as type three VWD.
SPEAKER_01Type three is the one where the symptoms are so extreme-like spontaneous bleeding into the joints that they simply cannot be ignored, even in a busy clinic.
SPEAKER_00Correct. But the mild type 1 VWD, which is far more common globally, it goes almost entirely undocumented in those regions.
SPEAKER_01Which obviously doesn't mean mild VWD magically doesn't exist in lower income countries. Right. It just means their health systems aren't built to capture it. The lab infrastructure isn't there, so the disease remains invisible. The prevalence rate you read in a textbook is often just a reflection of a health system's financial capacity, not a reflection of biological reality. Trevor Burrus, Jr.
SPEAKER_00That's spot on. And this brings us to the biology itself, which is perhaps the most surprising part of all this.
SPEAKER_01Okay, laid on me.
SPEAKER_00Well, we've been focusing on how human choices, our changing guidelines, our cultural stigmas, our unequal access to care, how they hide the disease.
SPEAKER_01Right.
SPEAKER_00You might assume that if we could just strip all that away, if we could just get everyone a blood test, the biology would give us a fixed, definitive answer.
SPEAKER_01Yeah, that's exactly what I assumed. If I have an inherited genetic bleeding disorder, shouldn't my blood test look exactly the same on Tuesday as it does on Friday?
SPEAKER_00It seems logical.
SPEAKER_01I mean it's in my blood, it's my DNA, it shouldn't move.
SPEAKER_00The reality is that VWF biology is incredibly dynamic. It is a moving target. Your blood test on Tuesday could easily look entirely different than your blood test on Friday.
SPEAKER_01Wait, really?
SPEAKER_00Yes, because von Wildebrandt factor is an acute phase reactant. This means the cells lining your blood vessels release more of it in response to stress.
SPEAKER_01Oh wow.
SPEAKER_00So VWS levels can rise naturally and completely mask a deficiency. Physiologic stress, vigorous exercise, inflammation, acute illness, and even just getting older all cause your VWF levels to spike.
SPEAKER_01Wait, so if a patient is just like terrified of needles and getting stressed out about the blood test itself, that anxiety could potentially alter the results of the test and hide their bleeding disorder.
SPEAKER_00Absolutely. The active testing can influence the test.
SPEAKER_01That is wild.
SPEAKER_00And it goes much further than just stress. Estrogen is a massive driver of VWF production. Pregnancy or estrogen exposure through things like birth control pills can significantly raise VWF levels, pushing a deficient person right up into the normal range.
SPEAKER_01That feels like a massive catch-22 for the women we talked about earlier.
SPEAKER_00It really is.
SPEAKER_01Because a woman with heavy menstrual bleeding might be put on birth control pills to manage the bleeding, but then if a doctor finally decides to test her for a bleeding disorder, the estrogen in the pill has masked the deficiency and her test comes back normal.
SPEAKER_00It happens constantly. And there's another fascinating biological twist too, which is your blood type.
SPEAKER_01Blood type.
SPEAKER_00Yeah. People with type O blood naturally have lower baseline VWF levels than people with non-O blood types. The protein actually clears out of their bloodstream faster.
SPEAKER_01That is wild. So you could have two people with the exact same genetic profile for this disease, but one has type A blood and one has typo blood. Right. And the type O person gets diagnosed because their natural baseline is lower, while the type A person's natural baseline props up their numbers and masks the disease.
SPEAKER_00Exactly. And because this biology moves so much, taking a one-time snapshot can lead to serious diagnostic errors, particularly overdiagnosis.
SPEAKER_01Overdiagnosis? How so?
SPEAKER_00Imagine a child who gets tested during a brief random period of low VWF. Maybe they had a borderline result just based on the day. Okay. They are handed the official label of type 1 VWD. For the rest of their life, they carry that burdensome, anxiety-producing label. Every time they go to the dentist, every minor procedure, there is panic, hematology consults, and expensive special protocols.
SPEAKER_01Right.
SPEAKER_00But if you test them again 20 years later, their baseline levels might be completely unequivocally normal.
SPEAKER_01But they're still carrying around this label. The disease isn't there anymore, but the diagnosis persists forever.
SPEAKER_00Good epidemiology has to account for both sides of the coin. The underdiagnosis caused by stigma and the overdiagnosis caused by fluctuating biology.
SPEAKER_01Okay, if the blood levels are fluctuating constantly based on stress, age, blood type, and estrogen, why don't we just bypass the blood levels entirely?
SPEAKER_00Go to the genes.
SPEAKER_01Yeah. Let's just go straight to the source and test the DNA. If it's an inherited disorder, shouldn't a genetic test give us a clear, binary answer?
SPEAKER_00Genetics is a powerful tool, but it is not a silver bullet, especially here. For the severe subtypes like type 2 and type 3 VWD, molecular testing is fantastic.
SPEAKER_01Okay, so it works there.
SPEAKER_00Yeah, the genetic mutations in those cases are highly penetrant, meaning if you have the mutation, you are almost certainly going to get the disease. But for the vast majority of cases like type 1 and those low VWF states in the gray zone, the genetics are remarkably murky.
SPEAKER_01Murky how? Isn't DNA destiny? If you find the mutated gene, don't you have the answer?
SPEAKER_00Finding a variant in the DNA doesn't mean you actually have a disease. Type 1 VWD has what geneticists call low penetrance and variable expressivity.
SPEAKER_01Let me stop you there. Variable expressivity, does that basically mean two people can have the exact same mutated gene, but one might bleed for days after a minor cut while the other person goes their whole life without a single symptom?
SPEAKER_00That is exactly what it means. Your VWF levels aren't controlled by just one switch. They are influenced by multiple different genes, compensating modifiers in your body, and environmental factors. Wow. You might have a genetic variant that theoretically causes low VWF, but your body compensates seamlessly and you never experience a single abnormal bleed.
SPEAKER_01So a genetic variant is just a biological possibility. Yes. It is not an expressed clinical disease. You can have the DNA for it and never actually be sick.
SPEAKER_00Precisely. Molecular prevalence describes possibility. Clinical prevalence describes an expressed real-world disease. VWD only truly emerges at the intersection of your genetics, your actual VWF levels, and your real-world bleeding symptoms.
SPEAKER_01So, what does this all mean for an actual person sitting on an exam table in a doctor's office? To bring all these abstract concepts into sharp focus, let's look at a real-world scenario to see how this hidden denominator in moving biology affects a single life.
SPEAKER_00Let's do it.
SPEAKER_01Let me set the stage for you. Imagine a 24-year-old woman. She finally gets referred to a hematologist because she wouldn't stop bleeding after a dentist pulled a tooth.
SPEAKER_00Okay, clappic trigger.
SPEAKER_01Right. The hematologist runs the blood test and her VWS activity comes back at 42. Remember, that's right in that controversial 30 to 50 gray zone we talked about.
SPEAKER_00Right.
SPEAKER_01She tells the doctor that she's had incredibly heavy periods since she was a teenager to the point where she has recurring iron deficiency. But, and this is key, she was never evaluated for a bleeding disorder until the dentist pulled that tooth.
SPEAKER_00This raises an important question, actually, several questions. This case perfectly synthesizes everything we've discussed today. It forces the clinician to ask six crucial context questions before making any kind of judgment.
SPEAKER_01What are they?
SPEAKER_00First, what definition of the disease is being used today? Second, who was tested? Third, what triggered the testing? Fourth, were bleeding symptoms required for the definition. Fifth, under what physiologic conditions were the measurements obtained? And sixth, who was never tested at all.
SPEAKER_01Let's apply those to her. The definition matters immensely because with the score of 42, the 2021 guidelines say she officially has VWD, but the 2024 guidelines say she just has low VWF.
SPEAKER_00Exactly. And consider what triggered the testing. It took a traumatic dental extraction to finally get her tested, even though she had been suffering from heavy menses and iron deficiency for a decade. A spawn. She was trapped in the hidden denominator for 10 years because her reproductive bleeding was normalized by the system.
SPEAKER_01And what about the physiologic conditions during the test? Her result was a 42, but was she stressed out at the dentist? We know stress raises VWF.
SPEAKER_00Right, it could have spiked.
SPEAKER_01If she was calm, maybe her true baseline is actually a 35. Or what if she's on birth control pills to manage those heavy periods? The estrogen raises VWF. If she ever stops taking the pill, her levels might plummet into the 20s, putting her in severe danger during surgery.
SPEAKER_00See, a 1% population statistic from a textbook doesn't diagnose this woman. Her risk depends entirely on the intersection of her specific bleeding phenotype, meaning her actual real-world symptoms, her current level of 42, her physiological state, and her future challenges. The clinician has to weigh a heavy choice. Will giving her the official label of type 1 VWD protect her by ensuring she gets specialized clotting medication during a future childbirth? Or will it burden her with unnecessary medical anxiety, insurance headaches, and surgical delays for a borderline condition?
SPEAKER_01It's a profound balancing act. Which brings us to the ultimate synthesis of our journey today. Epidemiology isn't just a hard number spit out by a computer. Not at all. It is a narrative. It's an output shaped by human definitions, by who has the financial and geographic access to health systems, by cultural stigmas around which symptoms we take seriously, and by shifting human biology. Good clinicians treat prevalent statistics as context, not as a verdict.
SPEAKER_00If you take away anything from this deep dive, it should be that the numbers you see in medical headlines, the one in ten or one percent of the population, they're never the whole story. They are fragile snapshots of a highly specific denominator taken under highly specific conditions.
SPEAKER_01I want to leave you with a final thought to mull over. We started this deep dive talking about the comfort of the X-ray, the clear, jagged line of a broken bone. The binary. Right. But we've seen today that our biological baseline is more like a river, constantly changing due to age, stress, hormones, and our environment, which makes you wonder about the future of medicine. We are entering an era of wearable technology that can constantly monitor our bodies.
SPEAKER_00Oh, that's an interesting point.
SPEAKER_01If our biology is always moving, what happens when we don't just test our blood on a random Tuesday at the doctor's office, but every second of every day through a wearable device? Will static disease labels like type one VWD eventually become obsolete?
SPEAKER_00It's very possible.
SPEAKER_01If our data becomes a continuous flowing stream, maybe these arbitrary diagnostic boundaries will just wash away completely. Are we treating the patient in front of us today or the ghost of their medical chart from a decade ago? Thank you so much for joining us on this deep dive. Keep questioning the numbers you see in the world, look for the hidden denominator, and we will catch you next time.