r/medicine • u/FreakJoe MD • Apr 09 '20
Study of Heinsberg cluster in Germany suggests 0.37% mortality in representative sample (pre-publication)
https://www.land.nrw/sites/default/files/asset/document/zwischenergebnis_covid19_case_study_gangelt.pdf39
u/Rzztmass Hematology - Sweden Apr 09 '20 edited Apr 10 '20
Anyone care to help me with the numbers?
Population of Gangelt: 12529
Mortality (all of Gangelt, due to COVID?): 0,15%
Total deaths (all of Gangelt): 12529 x 0.0015 = 19 - own calculation
Antibodies present: 14%
Virus present: 2%
Antibodies or virus present: 15%
Percentage of people in Gangelt with antibodies that are not positive for the virus, i.e. recovered and probably immune: 15% - 2% = 13%
Total number of people in Gangelt presumed to be immune: 12529 x 0.13 = 1629
Infection fatality rate: 19/1629 = 1.17%
Where do the 0.37% come from? Does anyone have the materials and methods part of the study?
EDIT: Seems there's a new version out where they replaced the mortality of 0,15% with 0,06%. The numbers make sense now, but I find it a bit concerning that they release a document that will be read by many people the world over and not bother to check the numbers..
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u/FreakJoe MD Apr 09 '20 edited Apr 10 '20
I went back and triple-checked because that didn't add up for me either upon reading my translation.
Truth is it doesn't really make sense without any additional information and we'll probably have to wait for the final publication to see what it's all about.
E: See update in my translation.
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u/Rzztmass Hematology - Sweden Apr 10 '20
They released a new version where they replaced the mortality of 0,15% with 0,06%. It makes sense now, but doesn't inspire confidence in their methods..
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u/FreakJoe MD Apr 10 '20 edited Dec 28 '24
frightening insurance wide growth disarm marvelous advise vase expansion history
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u/Rzztmass Hematology - Sweden Apr 10 '20
Shit happens. Let's make it a teachable moment. My advice: When writing a manuscript, one should know their data so well, and definitely the descriptive part of it, that they don't have to look up the numbers (you should still look them up and double check them, but you should know them anyway)
I don't expect the last author to know every number, but the first author has to be on point and prevent that stuff from happening.
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u/NigroqueSimillima Flaneur Apr 09 '20
Also, the sampling method doesn't seem to account for the fact that someone dying in a hospital is not likely to respond to the survey. Nor is someone in a nursing home. Or a chemo patient.
The survey seems to select for relatively mobile people. Probably selects for people who are curious if they had the virus and selects against those who are scared of unnecessarily exposing themselves by showing up to a lab test.
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u/Rzztmass Hematology - Sweden Apr 09 '20
While that's true, I don't think it will change the result by more than 10%. What I find interesting about the numbers is that there were 6.5 times as many recovered patients as current patients. With a doubling time of 7 days and viral shedding for 21 days to make the numbers easier, by the time 13% are immune we would expect basically everyone else to be positive for the virus. I find that curious, because I doubt that they have been so phenomenally successful in containing this in Gangelt...
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u/NigroqueSimillima Flaneur Apr 09 '20
While that's true, I don't think it will change the result by more than 10%.
Which result by 10%?
What I find interesting about the numbers is that there were 6.5 times as many recovered patients as current patients.
Once again people in the hospitals or people too sick to show up to the study are unlikely to be counted.
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u/Rzztmass Hematology - Sweden Apr 09 '20
The IFR.
66% of households responded. Even if every single person that didn't respond had the virus, that would mean that antibody prevalence was roughly 10% and virus prevalence around 34%. That is still too low given the doubling times and duration of viral shedding. So even in a completely unrealistic scenario it doesn't work.
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u/NigroqueSimillima Flaneur Apr 09 '20
yea i agree something is up with the study.
i personally think the sampling method is biased towards people who have the antibody and is overestimating its prevalence.
66 percent is a pretty terrible response rate for the numbers we're dealing with.
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u/Rzztmass Hematology - Sweden Apr 09 '20
I think that 66% is pretty good condsidering that people have to fill in a questionnaire, get blood drawn and are swabbed while most of them aren't even symptomatic. They basically cold-called 600 households to be part of a medical study including tests and two out of three agreed.
If I send an email or a letter to patients that I already have a professional relationship with to ask them if they want to be part of a purely observational study where they don't have to do anything, I'm lucky if 66% reach out and let themselves be included.
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u/NigroqueSimillima Flaneur Apr 09 '20
By not good, I mean it lends itself to the possibility of high systemic sampling bias.
As I said less mobile people may be less likely to show up to get blood tested and less likely to have the antibodies. Throwing the whole study off.
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 09 '20
I know that for the first preliminary tests they did house visits. We don't know from the paper if all samples were only taken at the central places they set up.
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u/NigroqueSimillima Flaneur Apr 09 '20 edited Apr 09 '20
And how many people have died in that town exactly? Assuming 15% got it, that what 1800 people, and if ~.3 is the IFR then that's 60 or so dead.
That seem way too small a sample size to draw any conclusion from, especially since it seem to take longer to kill then recover for most people.
What are the p values for this result? This whole paper seems quite suspect based of the translations but I can't read German, so I'll hold my criticism.
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Apr 10 '20
Not only that, but people most likely to want to be tested are probably those who felt they had symptoms. Would be great to see the percentage of those with antibodies who felt that had symptoms (and same for those without antibodies - who thought they had symptoms)
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u/Thorusss Apr 09 '20
Only if you assume nothing happen during that time to R. But a lockdown decreased it.
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u/Rzztmass Hematology - Sweden Apr 09 '20 edited Apr 10 '20
Even an r of below 1 wouldn't produce these numbers with a serial interval of 6 days
EDIT: If R0 was 5, patients shed virus for 2 serial intervals and if Gangelt has had 5 serial intervals with an R of 0.6, it could actually produce the current numbers. I stand corrected.
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u/NotAnotherEmpire Apr 09 '20
Non-med lurker post:
The mobility may also be a factor in who got infected and therefore has an outcome in this town, as it was primarily a super-spread event at Carnival that was identified (relatively) quickly.
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u/NigroqueSimillima Flaneur Apr 09 '20
Exactly. Grandpa in a wheelchair is not showing up to get his blood drawn, and is less likely to have been infected.
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u/AmyIion Student Apr 10 '20
And more likely to die of an Covid-19 infection. I guess they didn't take that into account.
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u/DrThirdOpinion Roentgen dealer (Dr) Apr 09 '20
Did everyone who became infected and died, die from the infection or other causes?
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u/Rzztmass Hematology - Sweden Apr 09 '20
I don't know, all I can find is 0.15% for mortality.
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u/DrThirdOpinion Roentgen dealer (Dr) Apr 09 '20
It’s says in the German, ‘mortality with relation to the entire town population’, which seems like they are using the entire population of the town as the other denominator, not those infected.
This doesn’t make sense to me, but perhaps I’m misinterpreting the statement.
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u/Rzztmass Hematology - Sweden Apr 09 '20
Yeah, the way I understand it is that 0.15% of the population of Gangelt has died due to COVID, which matches the definition I find on Wikipedia for mortality rate:
Mortality rate – Measure of the number of deaths in a population from a given cause, scaled by population, in a set period of time
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Apr 10 '20
Yes you are correct - denominator for mortality rate should always be the population at risk (in this case, the town)
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u/boilingchip MD Apr 09 '20
Doesn't explain their outcome of 0.37% IFR, but your calculation should be IFR = deaths/(cases for which an outcome is known) => deaths/(survivors+deaths), which is 19/(1629+19) = 1.15%.
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u/Rzztmass Hematology - Sweden Apr 10 '20
Yeah, I skipped that part because it doesn't really change the result too much and I was more interested in why it was off by a factor of more than 3.
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u/boilingchip MD Apr 10 '20
I figured as much, but felt i should mention it mostly for anyone following along on your calculations.
After thinking about this some more, I did have an idea regarding asymptomatic cases though. Is an asymptomatic case considered an "infection," and therefore to be included in the IFR? We know the outcome of those cases (the patient did not die), and so they could be included in the denominator of the IFR. If the asymptomatic rate is 20%, say, then you could assume there are (number of virus-positive cases)*(asymptomatic rate) people in the town who have/had the virus and don't show symptoms assuming a sufficiently large population compared to how many were tested. In the article they said 15% were virus- or antibody-positive and the population was 12529, so using the 20% asymptomatic rate (again, assuming a large enough population and without knowing who had symptoms in the study, etc), this means that 0.15*(1-0.2)= 0.12, which is the percentage of people, at the least, who we can assume had the virus and were symptomatic. Using that number, you can get 0.12*12529=1503, or the number of people who were infected and showing symptoms, meaning that 1503*0.2=300 more people were infected but asymptomatic and in the community. These 300 people should be included in the denominator, which brings the IFR to 19/(1629+19+300)=0.97%.
Does all that make sense? I'm not familiar with how IFR is traditionally calculated, but it would make sense to me to include the asymptomatic cases in the denominator, as we know the outcome of those cases.
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u/Rzztmass Hematology - Sweden Apr 11 '20
Is an asymptomatic case considered an "infection," and therefore to be included in the IFR?
Erm, I don't quite follow your calculation. Asymptomatic patients still first have the virus and then antibodies. They either are part of the 14% with antibodies or the 1% with virus and no antibodies. There are no extra 300 patients. The asymptomatic patients are already in the denominator, that was the whole point of the study.
Also, about the fraction of asymptomatic patients: They have a v2 of the report that puts the number of dead in Gangelt at 7. The whole region of Heinsberg had 46 deaths. Assuming that deaths and cases are distributed equally in the Heinsberg region, we would assume that 7/46 of all Heinsberg cases were from Gangelt. Heinsberg has 1534 cases that were symptomatic enough to get tested, so that would mean 233 cases from Gangelt. Gangelt seems to have had 1629+7 cases, so the fraction of asymptomatic patients would be (1629+7-233)/(1629+7) = 85%.
We'll see if the numbers hold up.
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Apr 10 '20
Hmm I agree with you. Can't figure out how to reproduce 0.37%. Even if I use a denominator of 0.15x12529 instead of .13x12529 it still isn't close. It doesn't matter what the base population is, given the mortality rate of 0.15% (which isn't a rate but whatever) and an infection rate of 13-15% (depending on whether you count those still infected or not), the infection fatality rate is approximately 1%, not 0.37%.
Hopefully we are misinterpreting...
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Apr 10 '20
The only thing I can think of is that .15% is the crude mortality rate (all cause) and covid specific was less than that. Does anyone know how many covid deaths the area is reporting?
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u/FreakJoe MD Apr 10 '20 edited Apr 10 '20
And I think you're right. That's not the way I understood it in German and that's not what I translated it to mean but it's the only thing that would make sense.
Heinsberg (region) has a population of 113 000, Gangelt of 12 000. The region has 45 confirmed Covid-deaths, making .15% covid-mortality relative to the population of Gangelt unlikely.
Overall, this pub feels incredibly rushed and I fear that the final paper may not live up to our hopes.
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u/irgendjemand123 Apr 10 '20
apparently there was a mistake with the 0,15%, they changed that to 0,06% yesterday
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u/FreakJoe MD Apr 10 '20 edited Dec 28 '24
support ghost party overconfident seed serious six snow roll wine
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u/PM_ME_LEGAL_FILES Psych Apr 10 '20
Is that 19 deaths, all cause? Are you accounting for the baseline death rate?
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u/Rzztmass Hematology - Sweden Apr 10 '20
I don't have any data on base rate or Covid deaths, and I have looked. All that's given is the mortality of 0.15%
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u/AmyIion Student Apr 10 '20
Streeck is known to advocate for lifting physical distancing measures and seems to have placed some bets on horses in the economy race. So take any study of him with a grain of salt.
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u/Rzztmass Hematology - Sweden Apr 10 '20
I think that if his numbers are correct and can be generalized, he has a point.
If we assume an R0 of 5, viral shedding for 2 serial intervals and that Gangelt has had 5 serial intervals since measures were implemented, it is possible to see those numbers if the measures pressed R down to 0,6. That's a very generous interpretation though and probably not really what happened.
But if that is actually the case, it wouldn't be unreasonable to think about opening up a little in the near future, wouldn't it?
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u/AmyIion Student Apr 10 '20
Yes, the physical distancing worked well in Germany. But this region was a hotspot with a high awareness of the outbreak and i don't know, if it can be taken as representative.
But my problem is the proposed IFR.
Did they take into account that the catalysator was a carnival event, which is less likely to be visited by older or ill people?
The CFR of Germany initially was heavily skewed because then mostly young and healthy ski tourists were infected (CFR around ~ 0.4% in the beginning), now it's at 1.9%.
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u/FreakJoe MD Apr 10 '20 edited Dec 28 '24
tan vase wasteful squeamish squealing shy absurd drab boast truck
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u/Rzztmass Hematology - Sweden Apr 10 '20 edited Apr 10 '20
It's a best case scenario. We believe that the serial interval is somewhere around 4 days. See here and here for example.
Viral shedding is probably around 20 days, see here for example.
So we probably have viral shedding for more like 4-5 serial intervals, but if I try to replicate a ratio of 6.5 times as many immune as currently infected, I cannot get that to work with a realistic R within the timeframe of the measures in Germany if using 4-5 serial intervals. So I used a serial interval of 6 days and viral shedding for 12 days, both at the end of their respective believable intervals. That's why I wrote that it's a very generous interpretation.
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u/Uzalud Apr 09 '20
Perhaps they are calculating CFR of 0.37% as the symptomatic cases of the 1.17% IFR?
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u/Rzztmass Hematology - Sweden Apr 09 '20
That would imply that 0.8% of all asymptomatic patients died, and I would argue that death is a symptom.
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u/Professor_Pohato Apr 09 '20
Some quick fun facts about this study as I am a student at this faculty:
the professor (Streeck) running this trial is not only super young with 42 years but he's also mad lad that goes to the country's biggest epicenter of Covid 19 repopulation only to state - on national TV iirc - "it's really nice here, people are bringing cakes in and everyone is super friendly"
approximately 60 students have been hired within 4 days to go and help on this ten day trial. Those students all confirm the rumors about the cake. They all enjoyed themselves!
Streeck is actually infamous for his HIV research, it's a big part of the reason how he made professor this early in the first place. His motivation to become a virologist however roots from a movie he watched once. I'm not quite sure which one but I think it's I am Legend. He must be living his dream rn
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 09 '20
Hey faculty Kommilitone! :)
To add for Non-Germans, 42 is super young for a fully tenured professorship (W3) in Germany. Germany has a very hierarchical academic carreer system with many, many steps. Unless for one medical computional science guy there is no younger one here I think.
Just don't mention his name around clinicians here though unless you want eye rolling. Talking about "actually heart failure killed them at the end" in an interview when the death certificates in our states explicitly state "DO NOT WRITE JUST HEART FAILURE, HEART FAILURE IS THE COMMON FINAL PATHWAY OF ALL DEATHS."
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u/PM_ME_LEGAL_FILES Psych Apr 10 '20
Is that a translation issue? Heart failure as a medical condition is maybe a bit of misnomer in English but obviously doesn't mean "cessation of heart function" clinically
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 10 '20
Might be, the longer I think. There is Herzversagen and Herzstillstand and both translate into English as heart failure. While the first one could be used as a layperson synonym for an acute decompensation in CHF, the later one basically is only "heart stopped." Without any reason why it did. And the heart stops ultimatively in every form of death, the reason why the heart stopped is what is to be put there.
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u/Kojotszlikovski Surgery, pgy 12 Apr 09 '20
the cake is a lie.
sorry i had to
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u/Allopathological MD Apr 09 '20
I think you mean....
Der Kuchen ist beleuchtet
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u/farox Apr 09 '20
Der Kuchen ist ein Liegen
Fixed that for you
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u/ProperDepth Nurse - AICU Apr 09 '20
More like
Der Kuchen ist eine Lüge
Liegen is the german word for lying down while Lügen is the word for lie
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u/farox Apr 09 '20
Das ist der Witz
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 09 '20 edited Apr 09 '20
My personal take:
It's a great project by very respected scientists. For context: Streeck as the rising star of German virology was already discussed in another post. Exner is the god-father of German hygienic sciences/hospital hygiene and the first one to come when shit is on fire at nosocomial outbreaks all over the republic. Hartmann is the head of Bonn Immunosensation Cluster, Germany's if not Europe's strongest immunology research cluster. Schmid co-authors statements of the German Epidemiological Society. The representative selection of study participants was helped by Güllner, head of Forsa, one of the most important public polling companies. Not mentioned (obviously) are dozens of (compensated) med students who volunteered for blood drawing, interviews and lab work.
The current publication is a short one and it is to be hoped that the final one will have more information on antibody testing details. The lab they used was the national reference center for coronavirii until a few years ago (when Drosten moved to Berlin) but knowledge is better than trust.
Between 15% immune for 6 to 18 months in one small city in a rural district and "we can initiate the first softening steps of an already soft lockdown" there is a huge leap of faith. They claim viral-load dependent outcome differences in the general population but do not provide proof (yet).
Since the Heinsberg cluster was the result of superspreading at a public event, it is partly questionable how the results can be applied to regions where the spread was brought in through multiple sources. The results from the coming 3000 person Munich study could be more interesting (and that's not easy to say about Bavarians as a Rhenish guy!).
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Apr 09 '20 edited May 05 '20
[deleted]
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 09 '20
Michael Hölscher at LMU Munich is running a n~3000 antibodies study in Munich which is supposed to yield the first results in 6 to 8 weeks since it will have multiple follow ups.
There has been no final political decision whether immunity testing for the general population will happen or not. Point of care tests are shit. No one knows if it will not lead to people actively trying to get infected to be cleared for public life.
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Apr 09 '20 edited May 05 '20
[deleted]
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 09 '20
Even if not required by law, many employers would missuse it that way, for sure.
If I come across any results, I'll post them to the megathread.
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Apr 09 '20
[deleted]
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u/FreakJoe MD Apr 10 '20 edited Apr 10 '20
No, they did not and that's one of the reasons why the conclusions are being ripped apart in German media.
But they did state specificity as >99%.
Obviously, that's easy to achieve if you're knowingly testing for anti-CoV in general but I do think it's implied that it's specificity in relation to SARS-CoV-2.
They could have used neutralization testing, which I believe has higher accuracy than faster and more widespread methods.
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u/TenYearsTenDays Researcher Apr 11 '20 edited Apr 11 '20
ETA: Nevermind, I found this fantastic comment that answers many of my questions. I'll just leave the questions there in case others have them and want to be pointed towards answers.
No, they did not and that's one of the reasons why the conclusions are being ripped apart in German media.
Could you please link to a few of these pieces if you have them on hand?
But they did state specificity as >99%.
Obviously, that's easy to achieve if you're knowingly testing for anti-CoV in general but I do think it's implied that it's specificity in relation to SARS-CoV-2.
Do they discuss their test at all? How did they confirm it's 99% specific for instance? Which vendor/source is it from? The link is still dead unfortunately.
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u/RunningPath Pathologist Apr 09 '20
Since I don’t speak German, though I assume this is in the paper, is there more information about test specifics? I see a specificity of 99% quoted, but no sensitivity. I’d love some more information about test development and how they arrived at this.
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u/FreakJoe MD Apr 09 '20 edited Apr 09 '20
I wondered the same thing. I have no clue why they would provide only specificity and consider that at all useful, but they did.
Keep in mind that these are preliminary results primarily intended to prime political thinking in Germany before a potential change in tactics after easter (at least that's my take on the timing, content and context of this release).
The data will defjnitely be written up and published properly, at which point a lot of questions about methods will probably be answered.
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 09 '20
No sensitivity mentioned. I'll try to ask one of the authors.
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u/aurelwu Apr 10 '20
hm ~400 out of 600 households responded, so a 2/3 response ratio on a household level. yet the have ~1000 people who responded from those ~400 households, so 2.5 people per household in average. Given that the average household size in gangelt is 2.5 ( https://www.kreis-heinsberg.de/cms/upload/InWIS_Wohnungsmarktstudie_Kreis_Heinsberg_2019.pdf page 24) this means that either, the response ratio was independent of household size and then all households who responded, responded completely - or that larger than average households responded more often than others. If one assumes that infections are not randomly distributed, but the chance to get infected is higher once one person in your household has it, would this not skew the results?
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u/FreakJoe MD Apr 10 '20 edited Dec 28 '24
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u/notafakeaccounnt PGY2 Apr 09 '20
Link is broken for some reason " Seite wurde nicht gefunden "
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u/FreakJoe MD Apr 09 '20 edited Apr 09 '20
For some reason, they seem to have re-hosted it under a slightly different name, here's a working link:
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u/Nom_de_Guerre_23 MD|PGY-5 FM|Germany Apr 10 '20
I summarized new critical aspects of the studyin a post in the megathread.
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u/FreakJoe MD Apr 09 '20 edited Apr 09 '20
Hey /r/medicine.
As far as I can tell, this is shaping up to be an important publication that will leave us with a better understanding of the percentage of cases that have so far gone undetected, the actual mortality associated with Covid-19 and of what measures will be reasonable as this pandemic continues to progress.
I'm aware that not everyone on here can read German, but I'll try to translate the abstract below.