Die Cluster Epidemiologie ist ein spannendes Teilgebiet der Epidemiologie, das sich mit der Untersuchung von Krankheitsausbrüchen in geografischen oder sozialen Clustern befasst. Die Ursache einer Krankheit zu finden , die in einer bestimmten Populationen oder Regionen gehäuft auftritt, ist immer schwierig und selbst wenn man die Ursache gefunden hat, ist sie kaum zu beweisen, da sich eine Re-Exposition verbietet.
Ich werde hier die Infektionskrankheiten einmal ausklammern, ebenso wie Berufskrankheiten oder die Ausbrüche mit bekannten Ursachen (Hiroshima, Bhopal, Seveso, …) und stattdessen einen bisher kaum benutzten Beweis versuchen, um ihn dann bei vier Clustern anwenden: Elbmarsch (Störfälle Kraftwerk), Umhausen (Radon Exposition), Barcelona (Staub von Sojabohnen) und Montchavin (Giftlorchel Vergiftung). Die ersten drei Fällen habe ich selbst oder über Institutsmitarbeiter erlebt, den letzten Fall kenne ich nur aus der Literatur.
In der Medizin gab es immer schon die “diagnosis ex juvantibus”, wenn die Diagnose durch den Erfolg oder Misserfolg einer therapeutischen Maßnahme gestellt wird. Bleibt die erhoffte Wirkung aus, kann dies die Verdachtsdiagnose widerlegen oder bestätigen, so etwa bei Infektionen wenn das Antibiotikum bei Verdacht auf eine bakterielle Infektion anspricht. Oder wenn bei unklaren gastrointestinale Beschwerden eine symptomatische Besserung nach Protonenpumpenhemmern die Refluxkrankheit sichert. Oder eine fragliche Allergien nach Antihistaminika anspricht.
Ich übertrage das Prinzip nun auf die Cluster Epidemiologie: Kann der Wegfall des vermuteten Risikofaktors auch den Krankheitsausbruch zum Erliegen bringen? Ist das dann ein gültiger indirekter Beweis?
Although promised, the supplement with the questions is missing and there is no information in the methods how the authors prompted – so basically useless as methods cannot be replicated.
And at the end, chatGPT is only a mirror of how good or bad these experts informed the public…
We know it for ages (1985) that 1,25-Dihydroxyvitamin D3 suppresses human T helper cells by blocking interleukin 2 (IL 2) production. The immune effects were our main argument 2001 against oral vitamin D supplementation of newborns as it may induce later allergy . It is now funny to find now a clinical trial that tests low-dose interleukin-2 in birch pollen allergy.
What initiated my change of mind was playing around with some AI tools. After trying out chatGPT and Google’s AI tool, I’ve now come to the conclusion that these things are dangerous. We are living in a time when we’re bombarded with an abundance of misinformation and disinformation, and it looks like AI is about to make the problem exponentially worse by polluting our information environment with garbage. It will become increasingly difficult to determine what is true.
“Godfather of AI” Geoff Hinton, in recent public talks, explains that one of the greatest risks is not that chatbots will become super-intelligent, but that they will generate text that is super-persuasive without being intelligent, in the manner of Donald Trump or Boris Johnson. In a world where evidence and logic are not respected in public debate, Hinton imagines that systems operating without evidence or logic could become our overlords by becoming superhumanly persuasive, imitating and supplanting the worst kinds of political leader.
At least in medicine there is an initiative underway where the lead author can be contacted at the address below.
In my field, the first AI consultation results look more than dangerous with one harmful response out of 20 questions.
A total of 20 questions covering various aspects of allergic rhinitis were asked. Among the answers, eight received a score of 5 (no inaccuracies), five received a score of 4 (minor non-harmful inaccuracies), six received a score of 3 (potentially misinterpretable inaccuracies) and one answer had a score of 2 (minor potentially harmful inaccuracies).
Within a few years, AI-generated content will be the microplastic of our online ecosystem (@mutinyc)
Hopefully the thread here on “farming and allergy” is now coming to an end. I tried to refute it for many years – last attempt in 2020
the main objection against the farming hypothesis is the interpretation of a negative statistical association as a “protective” effect. Only after thorough exclusion of alternative explanations, this interpretation may be justified.
but unfortunately missed another paper from the literature that had already been published in 2011, sorry for that.
With environmental exposures aside, at least 2 profound differences between farming and nonfarming families could be a threat to the validity of such investigations. One of these is the long-term selection of traits and genes in favor of the demanding living conditions of farmers because the agricultural lifestyle is often handed down within families. Referring to the “healthy worker effect,” we could expect certain disadvantages to be underrepresented in a farming population, giving rise to the concept of a “healthy farmer effect.”
Also the second point of Grabenhenrich has never been assessed
The other area expected to be different when comparing farming and nonfarming families constitutes behavioral patterns, lifestyle, and knowledge. For example, “soft factors,” such as health care use, symptom perception, and labeling, as well as access to and interest in health-related information, are most likely to be distributed dissimilarly. This disparity, in turn, could severely affect the response pattern in studies basing their case definition mainly on questionnaires. A temporal shift of these soft factors toward increased cautiousness and awareness has been assumed to contribute to the worldwide increase in symptoms of allergic diseases and, to a lesser extent, to the increase in clinically apparent disease.10, 11 Why should such a change be uniform in all parts of a population? Particular subgroups might be susceptible to catch up more rapidly. This phenomenon could be studied by identifying outliers in otherwise homogenous populations.
in the hope that journalists and politicians will never find it?
True heroes in epidemiology and public health are Semmelweis, Snow, von Pettenkofer, Doll & Hill, Hesse & Rehn but not a MD who can not even explain an Odds Ratio…
Here is a quick update on some genes of my recent asthma exome paper coming now from the 1 M exome paper published yesterday as a preprint.
loss of function variants IL1RL1. https://rgc-mcps.regeneron.com/gene/IL1RL1, 12 May 2023
Also ClinVar shows that the IL33 receptor is not “essential” making anti IL33 receptor antibodies like etokimab, itepekimab, tozorakimab a safe therapy although not being effective in any LOF mutation carrier.
The most interesting thing in the preprint is in supplemental table 2 with the s-het values for 16,704 genes. From that table I have selected my favorite target IL33 receptor together with TLR1, ALOX15, GSDMA, IL13 and IKZF3 ( BTNL2 could not be found in the list).
asthma exome https://rgc-mcps.regeneron.com/gene/IL1RL1, 12 May 2023
IKZF3 would be dangerous to be touched (see my 2008 commentary) while in the 2022 exome paper I also found only protective variants in the 5′-UTR but not any LOF variant – probably as IKZF3 is the only essential gene in the list.
So what’s next? I am still thinking how to reduce my exome set to the causal variants as half of the mutations are probably LD artefacts. And well, it would be super interesting to examine now two extreme inbred populations for their mutation spectrum, loosing either asthma variants by healthy (Amish) or diseased founders (Tristan da Cunha). Unfortunately there is little hope that this will happen – current science is built more on competition than collaboration.
report the impact of COVID‐19 lockdown in 365 Irish babies at 6 months of age enrolled in the CORAL study. These were a subset of 3773 infants born in two participating major maternity hospitals in Dublin between March and May 2020. Unfortunately only 10% of children participated, so families were self-selected. Allergic rhinitis was common in both mothers (36%) and fathers (30%) which is higher than reported by Allergy Ireland (26%) and explained by the authors that parental allergy is “higher than the general population, which may have contributed to parental desire to enrol in this study.”
A follow-up in March 2022 in 344 children consecutively shows higher food allergy (4.7% vs 3.5%, NS) when compared to an earlier cohort (BASELINE 2008). Atopic dermatitis increased of 15.5% in the BASELINE study to 25.3% in CORAL (no P reported) which is not unexpected given the interest of parents in an allergy study.
Maybe a short questionnaire at 2026 school entry would be informative than the current study? Nevertheless the authors needed now to analyze their stool samples sitting in the shelves. This is the content of the March 2023 preprint that has just been published. There may be an association of some bacteria with atopic dermatitis but in the end it is a useless result as the strongest risk factors for atopic dermatitis – parental history and/or FLG mutations – are missing from the presented models
At the end we can safely assume that the 2020 lockdown did not have any influence on allergy prevalence in Ireland.
Ich hatte direkt nach der Wende in Halle und Leipzig die erste Ost-West Allergiestudie* durchgeführt und dabei die verblüffende Entdeckung gemacht, dass es im Osten nicht mal halb so häufig Allergien gab.
Der Grund dafür war uns zunächst nicht klar, aber dann stelle sich doch bald heraus, daß es wohl die unterschiedliche Vitamin D Prophylaxe war – im Westen gab es tägliche niedrige Dosen ab der ersten Lebenswoche, im Osten wurde ab dem 2. Monat wenig hohe hohe Einzeldosen verabreicht. Wenn Kinder im Osten krank waren, dann fiel auch immer wieder die eine oder andere Dosis aus, auch wurde das Schema nach meiner Recherche nicht immer komplett durchgezogen. Leider haben wir uns damals aber nur die Impfpässe angesehen, nicht aber die im Nachinein wichtigeren Wiegekarten.
DDR Wiegekarte. Quelle https://www.ddr-museum.de/de/objects/1011262Westdeutsches Untersuchungsheft U2. Quelle https://www.g-ba.de/downloads/83-691-452/2017-05-11_GBA_Kinderuntersuchungsheft_Web-WZ.pdf
Die Befürchtung der Professoren Mai und Beuren in dem alten SPIEGEL Artikel über Vitamin D Nebenwirkungen haben sich zum Glück nicht bewahrheitet. Dafür aber stellte sich dann aber eine unerwünschte immunologische Wirkung heraus die damals noch nicht bekannt war.
Mit dem aus England bzw Amerika importierten Schema zur Supplementierung stiegen die Allergien an. In der BRD war das ab den frühen 60er Jahren , wie überhaupt die englischsprachigen Länder immer die höchsten Allergiehäufigkeiten hatten, da sie wegen der häufigen Rachitis auch viel konsequenter supplementierten (die Rachitis hiess früher einmal auch “englische Krankheit”).
Der Mechanismus der Allergieentstehung ist dabei nur teilweise aufgeklärt: Vitamin D ist jedenfalls immunsuppressiv mit vielfacher Auswirkung auf B und T Zellen was seit dem Nachweis des Vitamin D Rezeptors auf diesen Immunzellen wissen. Die Supplementierung stört offensichtlich die initiale Klassifikation ob ein Protein harmlos oder allergen ist.
Warum es aber auch schon 1989 Allergien im Osten gab? Nun, es war ja keine Vitamin D freie Zone, offensichtlich sensibilisiert man sich auch noch ausserhalb des überkritischen Intervals in den ersten Lebenswochen.
It seems that I missed an interesting 2017 paper that looked for disease-associated SNPs in canonical DR3 motifs. Only 7 out of 211 traits showed significant hits, one of these was self-reported allergy. When annotating these SNPs, there are only two genes: LINC00299 and TLR1
So are TLR1 & LINC00299 variant carriers more susceptible to vitamin D induced allergy?
LINC00299 (Long Intergenic Non-Protein Coding RNA 299) is a RNA Gene of largely unknown function, associated so far with allergy only on a genetic level in Framingham, href=”https://pubmed.ncbi.nlm.nih.gov/23817569/”>23andme and other studies. We don’t know so much here, the function of the long non coding RNAs
depends on subcellular localization. Depending on their niche, they specifically interact with DNA, RNA, and proteins and modify chromatin function, regulate transcription at various stages, forms nuclear condensation bodies and nucleolar organization. lncRNAs may also change the stability and translation of cytoplasmic mRNAs and hamper signaling pathways. Thus, lncRNAs affect the physio-pathological states and lead to the development of various disorders, immune responses, and cancer.
The TLR1 genetic association is found by many genetic studies, while the clinical association is probably more by an infectious origin. TLR1 is a pattern recognition receptor with a specificity for gram-positive bacteria and also included in my forthcoming exome paper as a protective factor for asthma/allergy. And we are also close to my earlier review of vitamin D, the microbiome and allergy…
Does any co-infection response during first vitamin D exposure influence allergic sensitisation? There are indeed some hints of an short-lived effect of lung group 2 innate lymphoid cells (ILC2s)
Laboratory mice cohoused for 2 weeks had impaired ILC2 responses and reduced lung eosinophilia to intranasal allergens, whereas these responses were restored in mice cohoused for ≥2 months. … These findings suggest that ILC2s respond dynamically to environmental cues and that microbial exposures do not control long-term desensitization of innate type 2 responses to allergens.
Again: The hygiene hypothesis was not born by David Strachan and well, there are more cracks of the hygiene hypothesis.
“The trouble is, as soon as you use the words ‘hygiene hypothesis,’ the word hygiene prejudges what the cause is,” says Bloomfield. To the public, “hygiene” is interpreted as personal cleanliness: washing hands, keeping food clean and fresh, sanitizing the home. However, because the hypothesis has been largely uncoupled from infections, the idea that we need to be less hygienic is wrong. Relaxing hygiene standards would not reverse the trend but only serve to increase the risks of infectious disease, says Bloomfield. The term “hygiene hypothesis” also fails to incorporate all of the other factors now linked to the increase in immunoregulatory diseases.
I expect that five years after mandating “super hygiene” during COVID-19 we can finally bury the hygiene hypothesis.
Just tried citationgecko.com on a topic that I have been working on for 2 decades. It will find rather quickly the source paper, much faster than reading through all of it. Unfortunately reviews are rated to be more influential than original data as Citation Gecko picks articles with many references.
So let’s have a more detailed look at farm parents. It can be drilled down to the question if parents are also “protected” or it is more likely that some affected parents just moved away. Here are 13 studies that included information about farm parents. Continue reading Parental allergy history at farms→
What is even more remarkable is the challenging keynote of the Xth World Congress of Psychiatric Genetics in The Palais des Congre ́s Brussels, Belgium October 9 –13, 2002 by Irving Gottesman [+2016], the father of epigenetics in psychiatry. He wrote there
We cannot escape the history of our field and are constantly guided today by the accumulation of facts with either positive or negative valences from our past. But when did the clock start—with the domestication of animals, with Galton’s musings and amoral passion for data collection about individual differences in behavior, or with the initially objective scientizing of Mendelism applied to schizophrenia but ending with a Nazi-tainted albatross around the neck of psychiatric genetics. In regard to the long quest for the distal and genetic (partial) causes of mental diseases, the conclusion that both genetic and environmental factors, none yet known in detail, provide the distal causes of mental disorders—that statement is too general to be of use to making further progress. What is needed is a confrontational approach based on evidence collected from competing ‘schools of thought’, and then reconciliation before some kind of omniscient and impartial Science Court.
I couldn’t agree more. What is needed is a confrontational approach based on evidence collected from competing ‘schools of thought’, and then reconciliation before some kind of omniscient and impartial Science Court.
It seems that the respiratory tract isn’t so much influenced by rare gene variants but that there is a strong effect in the immune system.
And there is another interesting fact.
…Surveying the contribution of rare variants to the genetic architecture of human disease through exome sequencing of 177,882 UK Biobank participants …if we look at the …. European population who are carriers of a filaggrin (FLG) PTV, we find those carriers have significantly higher risk for well-known associations, such as dermatitis … and asthma … Concomitant increases in vitamin D levels suggest … increased sensitivity to ultraviolet B radiation.
So far, I have only assumed an asthma/allergy priming effect of oral vitamin D in the newborn gut. This paper now argues for an increased vitamin D sensitivity also in the skin of FLG dermatitis patients which is interesting given the largely contradictory data of serum vitamin D and atopic dermatitis. Maybe dermatologists should focus their research more on skin and local vitamin D turnover?
-II-
The most prominent IL33 variant carried by over 2,300 people is splice acceptor 9-6250473-G-C followed by 600+ individuals with splice donor 9-6250600-G-T.
There are not too many carriers of this variant by the sheer amount of 177,882 participants. We nevertheless know already something about the seven IL33 splice variants since 2012.
Novel Splice Variants of IL-33: Differential Expression in Normal and Transformed Cells Journal of Investigative Dermatology (2012) 132, 2661–2664; doi:10.1038/jid.2012.180
Fig 3A Smith et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma, PLoS Genetics 2017 – describes the splice site as NM_001199640:exon7:c.487-1G>C or rs146597587-C
So I did a sequence match to compare the new finding with these older publications.
own sequence match exon7 using data from dbSNP, UCSC GoldenPath and Uniprot – reference is hg19
Indeed, the 2017 paper already described rs146597587 which is probably identical to the splice acceptor 9-6250473-G-C in Astra UK Phewas (genome positions do not match – I used hg19 while I don’t know the Astra reference) . Astra says also c.613-1G>C while rs146597587 is just upfront of my codon 205 (3*205=615) whatever that means.
The Astra UK Phewas at least confirms the Iceland paper above
rs146597587-C associates with lower eosinophil counts (ß= -0.21 SD, P = 2.5×10-16, N = 103,104), and reduced risk of asthma in Europeans (OR = 0.47; 95%CI: 0.32, 0.70, P = 1.8×10-4, N cases = 6,465, N controls = 302,977). Heterozygotes have about 40% lower total IL33 mRNA expression than non-carriers and allele-specific analysis based on RNA sequencing and phased genotypes shows that only 20% of the total expression is from the mutated chromosome. In half of those transcripts the mutation causes retention of the last intron, predicted to result in a premature stop codon that leads to truncation of 66 amino acids.
So it is basically a rediscovery meaning that we reached saturation.
This is basically an update of my 2017 Allergy paper where I asked about sequelae of early vitamin D supplementation.
Two extensively examined hypotheses are the hygiene hypothesis (lack of protective bacterial exposure which leads to subsequent allergy) and the vitamin D hypothesis (early vitamin D supplementation sensitizes newborns against allergens) … The interesting question is: Are these concepts exclusive? … There is some preliminary evidence that – like many other environmental factors –vitamin D may modify the human microbiome.
Only yesterday a paper popped up during a presentation of Amelie Baud about the influence of social partners and the gut microbiome. This 2018 study tested gut microbial composition from 16S rRNA sequencing during the first year of life and subsequent risk of asthma in 690 participants
1-year-old children with an immature microbial composition have an increased risk of asthma at age 5 year … the microbial composition was not affected by maternal asthma status suggests that only susceptible children, exposed to inappropriate microbial stimulation during the first year of life, may express their inherited asthma risk …. The five most discriminating indicator OTUs for each cluster were identified for PAM cluster 1 as Enterobacteriaceae, Staphylococcus, Streptococcus, Bifidobacterium and Enterococcus, and for PAM cluster 2 as Faecalibacterium, Bacteroides(x3), and Anaerostipes … the risk of developing persistent asthma was increased (adjusted hazard ratio (aHR) 2.87 (1.25−6.55), P = 0.013) if the microbiome remained in PAM cluster 1 at age 1.
IMHO this doesn’t look very much like direct microbiome effects but some colliding factor. The authors discuss cesarean section-birth and antibiotics as relevant factors while I wonder why the last author (who is a known pro vitamin D lobbyist ) doesn’t take into account vitamin D here?
there was a significant association between community composition and vitamin D supplementation at the genus level. The vitamin D group had a higher abundance of genus Lachnospira, and lower abundance of genus Blautia (linear discriminate analysis >3.0). Moreover, individuals with 25(OH)D >75 nmol/L had a higher abundance of genus Coprococcus and lower abundance of genus Ruminococcus compared to those with 25(OH)D <50 nmol/L.
Vitamin D supplementation significantly increased gut microbial diversity. Specifically, the Bacteroidetes to Firmicutes ratio increased, along with the abundance of the health-promoting probiotic taxa Akkermansia and Bifidobacterium. Significant variations in the two-dominant genera, Bacteroides and Prevotella, indicated a variation in enterotypes following supplementation.
So is the microbiome just an indicator of vitamin D exposure in genetic susceptible children?
