N=1: Symptom vs. Syndrome

Previously in this series:

N=1: Introduction
N=1: Single-Subject Research
N=1: Hidden Variables and Superstition
N=1: Why the Gender Gap in Chronic Illness? 


People like to argue about whether obesity is a disease. Does it require treatment, or is it more of a social problem? But obesity isn’t a disease. It’s clearly a symptom. 

Think about it like this. Fatigue is a symptom, and it’s a symptom of many things. Fatigue can be a symptom of everyday decisions — you can be fatigued because you stayed up until 3 AM last night playing Octodad: Dadliest Catch. It can be a symptom of substances, like alcohol or Benadryl. It can be a symptom of conditions, like anemia or concussion. And fatigue can be a symptom of diseases, like mononucleosis, Parkinson’s, or lupus. 

Similarly, a person can be obese for a number of different reasons. Obesity is a symptom of many different conditions. You can be obese because of a brain injury. You can be obese because of a thyroid issue. You can be obese because you’re taking a drug like haloperidol or olanzapine. And while there’s still a lot of dispute over the source of the global obesity epidemic, you can be obese because of whatever cause(s) are causing that. 


Things get confusing when you try to treat a symptom like a disease. 

Think about fatigue. If your friend is tired from playing video games until the wee hours of the morning, the correct treatment is for them to play video games while pretending to fill out spreadsheets at work, like a normal person. If they’re fatigued from drinking merlot or taking Benadryl, the only real option is to have them wait until the drug wears off (or take an upper, but that’s not really recommended). If they’re anemic, then they need to get more iron. Et cetera.

Similarly, we don’t know how to treat the general obesity we see in the obesity epidemic. But we do have treatments for obesity caused by thyroid disorders or brain tumors. And we shouldn’t be shocked if treatments that work for obesity caused by thyroid disorders don’t work for the obesity caused by brain tumors, or don’t work for the widespread obesity we see today.

Because a symptom can have many different causes, just looking at the symptom won’t always tell you the cause. And if you don’t know the cause, then you may not know the right treatment, because you don’t know the etiology; you don’t know how the cause connects to the symptom, at what points you can intervene, and what kinds of interventions might be helpful.

This is pretty bad — even when there’s a finite list of possible causes, it’s hard to look at a symptom and figure out which of its causes are responsible. 


Many chronic illness symptoms are nonspecific. Per Wikipedia

Nonspecific symptoms are very general and thus can be associated with a wide range of conditions. In other words, they are not specific to (not particular to) any one condition. Most signs and symptoms are at least somewhat nonspecific, as only pathognomonic ones are highly specific. But certain nonspecific signs and symptoms are especially nonspecific and especially common. They are also known as constitutional symptoms when they affect the sense of well-being. They include unexplained weight loss, headache, pain, fatigue, loss of appetite, night sweats, and malaise.

This means that people who are diagnosed with the same chronic illness could have similar experiences, similar symptoms, with entirely different causes. If you have headache/pain/fatigue, you might reasonably assume that someone else with headache/pain/fatigue has the same illness, and that it was caused by the same thing. You might assume that the same treatments will work for both of you, that your illness would have the same cure. 

But headache/pain/fatigue are all nonspecific — they can all be caused by a zillion [sic] different things. So someone who shares your exact symptoms may have the exact same experience but for totally different reasons. If this is the case, the treatments that work for one of you may not help at all for the other.

(Even worse, palliative treatments will tend to work for both of you, since they treat the symptoms directly, and this will make the two conditions seem even more similar. But curative treatments that work for one of you won’t work for the other, since your conditions have different root causes.)

Let’s consider migraines. Migraines can definitely be caused by hormones. Some people have migraines only during certain parts of their period (about 7-14% of women, according to Wikipedia), or only when pregnant. Migraines can also be caused, or at least partially caused, by triggers like stress or certain foods.

But there are also people who get random mystery migraines on a regular basis, with no apparent trigger. Presumably these are caused by something, but it’s not something obvious like stress or hormonal cycles or being pregnant. So clearly migraines are a symptom, not a disease — they can be caused by several different things.

All this to say that finding the “cause” of migraines may be the wrong framing. There may be no more single cause of migraines than there is a single cause of car accidents. Some accidents happen because the driver wasn’t paying attention (and many people think of this as prototypical). But some accidents happen because the road is icy. Some accidents happen because the driver had a seizure and lost control of the car. Some accidents happen because the vengeful spouse of the man you killed in El Paso 15 years ago has finally tracked you down and cut your brake lines. 

Not that we would know anything about that! We’ve never been to El Paso, officer, we swear.

There is no single cause of car accidents. They are more like a symptom. All car accidents look much the same — broken glass, tire marks, people yelling. Most car accidents have similar proximal causes — unless it was an intentional ramming, it happened because someone lost control of their vehicle. But despite these apparent similarities, car accidents can have wildly different original causes. They happened for different reasons.

Consider chronic fatigue syndrome (CFS). Most people assume that CFS is a disease, and that everyone with CFS has it for the same reason, that there is a single cause. But maybe CFS is more like a symptom (obviously “syndrome” is literally in the name). If so, the search for the “cause” of CFS is a mug’s game, since it is caused by many different things. If you go around assuming there is one cause of CFS, one etiology, you are going to end up very confused. 

Or consider irritable bowel syndrome (IBS). Most people seem to be aware that IBS is not really a single diagnosis, and probably is a term used to describe all sorts of different, unrelated things. E.g. “Some people just have trouble with their stomachs. When they have trouble and we don’t know what is causing it, we just call it IBS. So you have IBS.” Even so, the label kind of implies that there is a similarity of some sort, and suggests that maybe there will be some similarity of treatment and of cure. But this may be misleading.

If nothing else, the shared label means that all these people are likely to end up in the same groups or the same communities “for people with IBS”. If someone makes a post like “this treatment cured my IBS”, you can be sure other people will respond with, “well it didn’t cure *my* IBS”. This is guaranteed to be the source of a lot of confusion.

We think that most unsolved chronic illnesses are probably like this — most of them are probably different diseases with different causes that happen to look very similar.

Compare it to the anthropic principle if you like — diseases that present in a consistent way and have a single cause are easy to figure out, so they tend to be cured and don’t tend to be on the list of unsolved chronic illnesses. But diseases where a number of very different causes present very similarly will be quite hard to figure out, and are likely to remain mysterious for a long time. So things that are unsolved and have been unsolved for a while are more likely to have multiple causes. 

(Though even simple illnesses with precise single causes, like scurvy, can be devilishly difficult to figure out, so take this argument with a grain of salt.) 


Single-subject (aka N=1) research can be really powerful. But when it comes to cases like this, you have to be very careful. Even if you do a very rigorous single-subject experiment, and provide strong evidence that some treatment works for you, you’ve only really provided evidence that it works FOR YOU. It may not work for anyone else. 

If the treatment that works for you doesn’t work for most other people with your diagnosis, that’s actually somewhat informative. We can see why some people would find it discouraging, but it suggests that the illness you have “in common” is actually two different illnesses, or at least two substantially different presentations. That means it gets us one step closer, a small step but a step even so, to figuring out what is going on with your illness, and maybe getting a cure or treatment for everyone.

If you end up with Treatment A that works for 20% of people with your condition, and Treatment B that works for 50%, and there’s basically no overlap, you’re off to a great start. You can start looking for anything that the Treatment A people have in common that’s never found in the Treatment B group, and vice-versa. If you find something (“holy cow, everyone who liked Treatment A has Irish heritage!”), you can start directing people to try the treatment that’s most likely to work for them. 

Even if you find nothing in common within the groups, you’re still in good shape. There are only two treatments, and we know that Treatment B works for more people. Newcomers can start by trying B, and if that doesn’t work, they can try A next. If neither work, then they are in the other 30% with no discovered treatment. But it’s still progress in general, and you can start putting your efforts towards finding treatments C, D, E, etc. 

It may be tempting to jump ahead and start looking for differences now, before we have treatments that distinguish between various groups, and there is some merit in this idea. If we find that half of people with IBS tend to have bloating with no reflux, and the other half tend to have reflux with no bloating (or whatever), that’s a pretty interesting sign, and will probably end up being useful. 

But this approach doesn’t usually seem to work.[1] Probably this is because clustering by symptoms isn’t useful; or when it is useful, it will already be obvious. Different causes can present with identical symptoms, as we’ve been discussing. But IDENTICAL causes can also sometimes present with DIFFERENT symptoms! There’s no royal road, no way to cut this knot for sure. You just have to be careful. 

The real enemy here is the confusion (lit. fusion together of different things; “(transitive) To mix thoroughly; to confound; to disorder.”). Talking about “having CFS” or “having IBS” is handy, but when it comes to diagnostics, more detail is better. You may be surprised to discover that someone with the same diagnosis as you has almost nothing else in common. And even when you have every symptom in common, don’t confuse this for a common cause. Your friend may also have migraines, but don’t be shocked when the thing that worked for you doesn’t work for her.

Remember that car crashes all have similar presentation. In true diagnostic fashion, they usually show three or more of the following symptoms: broken glass, injured driver(s), skid marks, bent fenders, police on scene, plastic debris on the road, etc. Take two Geico and call me in the morning. 

it’s ok, this lizard is a doctor

If you only did an analysis of symptoms, you might think that all car crashes have the same cause. An analysis of symptoms would suggest just one group. But we know that’s not the case — car crashes can happen for many different reasons, and even car crashes with very different causes will usually have very similar symptoms. 

Maybe if you are a genius detective and you know just what to look for, you can tell them apart — maybe a car crash caused by a seizure will show signs of uncontrolled driving well before the point of impact, while a car crash caused by excessive speed will have longer, straighter skid marks on the blacktop. But you certainly won’t be able to discover the different causes of car crashes by going down a checklist of “was there broken glass?”, “were there skidmarks?”, “were the drivers injured?”, etc.

If you add in criteria like “how long were the skidmarks?” you might get closer. But you’d have to understand the causes well enough to add that question in the first place.  


[1]: If you know of any examples of looking at a disease, looking for patterns in its symptoms, and finding that it is really two diseases (or something similar), we’d be interested to hear about that, since we can’t think of any examples where this approach has worked.

7 thoughts on “N=1: Symptom vs. Syndrome

  1. Gilly Joconde says:

    Re: disease turning out to be multiple diseases.

    I can’t think of a past example, but it seems like Ehlers Daners is in the process of becoming multiple distinct syndromes. There are already pretty different subtypes.


  2. Shannon says:

    Maybe not exactly what you’re looking for, but skincare is actually the first place I internalized same symptom =/= same treatment. It’s all N=1 as far as skincare goes! BUT….people in r/skincareaddiction are scary good at looking at people’s acne and figuring out when its caused by FUNGAL rather than bacterial causes. Fungal acne required anti-fungal treatments, of course! Even harder for my eyes to discern, is when people can clock that acne that otherwise looks bacterial, is HORMONALLY caused…IIRC, it tends to cluster on the chin area, correlated with menstrual cycle, and can be effectively treated by consuming types of tea that increase certain hormones (?) at certain times of the month. For people without fungal acne or hormal acne, those treatments don’t do basically anything and you’re back on the dermatologist recommended routine route! And that’s a branching tree if I’ve ever seen one…


  3. Anon says:

    It is worth noting that, in many cases, the available treatments for the symptoms are safer and more effective than the available treatments for the “root cause.” Compare epilepsy, which can be treated with either medications (for the symptoms) or brain surgery (for the root cause). Needless to say, doctors usually try the medications, with the surgery only as a last resort.


  4. nth_degree says:

    I have a traumatic brain injury, sustained as a pre-pubescent. Over the past few years (mid-30s, trying to get pregnant), I’ve realized just how much this TBI impacted my hormones, shining a bit of light on why I was so different from my peers as a teen. Anyway, brain damage is a sort of lifelong N=1 experiment.

    Liked by 1 person

  5. JG says:

    I think diabetes mellitus is a clear example of a disease that, after careful examination, turned out to be two diseases. You could even throw diabetes insipidus into the mix and say it ended up being three diseases.

    Supposedly, back in the day in China and India they had divided diabetes into type 1 and 2 when they noticed that type 2 was a disease of fat wealthy people.

    Later, in the 1700s you have Dobson talking about how some people died very quickly from diabetes while for others it was a long term disease.

    Even later, when they started using insulin to treat diabetes, they realized that people were reacting differently to different amounts of insulin which led to Himsworth’s classification of two types of diabetes mellitus, insulin sensitive and insulin insensitive.


  6. I thought this had happened with SIDS. My CNM told me that though reported ‘SIDS’ deaths are trending downward, it’s not because fewer babies are dying, it’s because deaths that would have previously been classified as SIDS deaths (as a generic ‘hey we don’t know why but this baby suddenly died’) are being classified as something else as they are identifying individual diseases and underlying causes.


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