Category Archives: Genetics

Schutz vor Allergie auf dem Bauernhof: Ist das zentrale Paradigma falsch?

Keine Frage – Lebensbedingungen auf Bauernhöfen sind anders. Mehr Tiere, mehr Dreck, mehr frische Luft, alles ist anders als in einer Großstadt. Das kann auf Selektionsbedingungen zurückzuführen sein, z. B. gut  zu sehen in einer der ersten Studien vor 30 Jahren.

Clin Exp Allergy. 1999 Jan;29(1):28-34. https://doi.org/10.1016/S0140-6736(01)06252-3

Auch die Eltern hatten schon weniger Allergien, und damit logischerweise auch die Kinder.

Wenn man genau hinschaut, dann haben alle Bauernhofstudien doch immer wieder dieselbe Argumentationsstruktur – weil die Bedingung X dort so, dann kann die Folge Y dort auch auf die Bedingung X zurückgeführt werden. Immer mehr Beschreibungen von X machen die Story aber nicht glaubwürdiger.

Keine der jemals beschriebenen Bedingungen X, ist aus dem Bauernhofmilieu heraus aber auch auf allgemeine Situationen mit Folge Y übertragbar gewesen, von einem einzigen weitgehend verunglückten Versuch einmal abgesehen. Keine einzige Bedingung X  ist nach 30 Jahren verallgemeinerbar, so dass nun alles doch nach einer einzigen Blase aussieht.

Natürlich hat ein hoher Endotoxin Spiegel auf den Bauernhöfen eine bestimmte Wirkung –  zumindest bei einigen Menschen und bei einigen Mäusen – aber ist das wirklich  mehr als ein modifizierender Faktor?

Da Lebensbedingungen auf dem Bauernhof angeblich protektiv sind, müsste auch mal ein einziges Kind präsentiert werden, das eigentlich eine Allergie haben muss, weil seine beiden Eltern allergisch waren.  Aber dieses Kind gab es nie, weil auch schon die Eltern keine Allergien haben.

 

Farming and allergy prevention could be caused by Berkson’s fallacy

Lets look at the Wikipedia definition first

Berkson’s fallacy is a result in conditional probability and statistics which is often found to be counterintuitive, and hence a veridical paradox. It is a complicating factor arising in statistical tests of proportions. Specifically, it arises when there is an ascertainment bias inherent in a study design … The most common example of Berkson’s paradox is a false observation of a negative correlation between two positive traits, i.e., that members of a population which have some positive trait tend to lack a second.

The original example is developed unsing the example of an hospital based group of patients. The only thing to know is that diabetes is a risk for cholecystitis in the general population.

Any given hospital in-patient without diabetes must have another disease (otherwise he would not be there), for example cholecystitis. And by definition this will be cholecystitis without diabetes caused by some other risk facors (female, fat, forty…) So in this group of in-patients there maybe a spurious negative association between cholecystitis and diabetes.

My example here is with families who are living on farms. Since around 1960  [Leynaert 2001] there is this interesting observation that farming families have less allergy, an effect that I found back in 1989 and that is most likely a healthy farmer effect.
This selected farm population has a lower allergy prevalence and of course their children will also have less allergy. All the negative correlations (that are interpreted as protection) with endotoxin, microbiome, etc could be caused by Berkson’s fallacy. The observation will also be even replicated as the same selection criteria are also present in the replication sample.

Many more cognitive biases could also be involved: anchoring, availability cascade, confirmation and expectation bias and of course: law of the instrument.

What is wrong with the 2011 NEJM paper?

N Engl J Med 2011;364:701-9 is another paper with 1000+ citations  that had a lasting impression on some but not all people.

First, I can’t remember of any study with such an enormous selection bias  where >94% of individuals have been lost.

Second, we should not forget that farm is not protective per se – farmers may just avoid a known allergy risk factor.  The PARSIFAL participants in this study included Steiner schools — anthroposophic medicine mostly avoids vitamin D (another ref). This is of course a major issue for any cross-sectional study that doesn’t take into account the temporality of events.

Third, in PARSIFAL dust from children’s mattresses were collected by vacuuming — it is not very likely that many helminthic eggs were transported  from stable to bedroom. In GABRIELA, only airborne dust samples  were collected which may miss helminth eggs although being highly present in stable dust.

Fourth, more  microbial exposure and more fungal taxa on farms are a trivial finding.

The inverse associations of the diversity scores with asthma were not confounded by status with respect to living on a farm because adjustment did not change the respective point estimates for asthma (Table 2), although the associations became nonsignificant.

Small sample size, borderline p-values even after a long fishing expedition? And what do these strange “probability” plots  really show – the probability of asthma or the probability to live on a farm?

N Engl J Med 2011;364:701-9 Figure 3 Does it refute any general effect of diversity?

The plots are misleading if adjustment for farm living does not change the parameter estimates for bacterial/fungal diversity. Does that really mean that farm are irrelevant?

Sixth – even many years later, the main findings of this study could not be replicated. There is not any single study that shows listeriosis (Listeria) or diphtheria (Corynebacterium)  to be protective.

Does a healthy worker effect explain the “allergy protection” at Bavarian farms?

Unfortunately most studies in the farming environment did not report the prevalence of parental history nor did they report the effect size of parental risk in the farming population. This is, however, a critical issue as the so called healthy worker effect HEW may be a rather trivial explanation of the results.

Specifically, it is a sampling bias: the kind of subjects that voluntarily enroll in a clinical trial and actually follow the experimental regimen are not representative of the general population. They can be expected, on average, to be healthier as they are concerned for their health [or as ill people already dropped out]

At least Braun-Fahrländer 1999 reported that allergic parents were seen much less at farms: allergic rhinitis 12.7% versus 29.4% (P=0.001). A history of allergy therefore is no more a risk factor as it is in the general population.

Leynaert 2001 showed only a slightly reduced prevalence of “allergy” (39.1% vs 41.5%, NS) while her table 4 is most interesting. The association started only after year 1960 which points towards misclassification as far as the analysis is not stratified by year of birth.

Remes 2002 showed a dose dependent effect decline between farming (36.2%) and controls (31.6%, P=0.075),

Perkin 2006 also found some significant lower prevalence in farmers 47.3% versus 57.7%, P<0.001.

A HWE is therefore likely.

In total, I found indeed six studies (Thelin 1994, Braback 2006, Chenard 2007, Thaon 2011, Elholm 2013 and Spierenburg 2015) that examined in detail a possible relationship of HWE, allergy and farming. Unfortunately the examination period in five of these studies is too short for any conclusion with Braback 2006 being the only reliable study.

Also from this study, we can safely conclude, that there is a significant HWE.

 

Predicting life span – an ethical nightmare

One of the most fascinating articles earlier this year was the report of Timmers et al.  about the “Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances“.   The British-Swiss-Estonian-Chinese-US collaboration identified by genome-wide SNP association of 1 million parental lifespan some new genes (ABO, ZC3HC1, and IGF2R) and replicate others (CDKN2B-AS1, ATXN2/BRAP, FURIN/FES, ZW10, PSORS1C3, 5q33.3/EBF1 and FOXO3).

Most of the variance is explained by disease variants that lead to dementia, cardiovascular disease, and lung cancer – of course people die of disease and not by bad genes. So whether correct or not, what worries me more is the construction of polygenic hisk scores that show a mean lifespan difference of around five years of life across the deciles.

This may become an ethical nightmare whenever treatment allocation will dependent on a polygenetic risk score that is largely irrelevant in an individual.

Climate crisis and cognitive dissonance

There is an interesting twitter thread by @Psychologists4F about news concerning the climate crisis and how we respond to the cognitive dissonance – the mental discomfort or psychological stress experienced by a person who holds contradictory beliefs or values. There are at least four possibilities how to respond to it

  • Change the behavior (“reduce, refine, replace”)
  • Changing the conflicting situation by just ignoring it
  • Justify own behavior by pseudoexplanations, pointing to others
  • Deny information by devalueing the source

During the discussion the question was asked why the political right wing tends to ignore the dissonance. One commentator points towards a study in Current Biology that may have answer to that. Continue reading Climate crisis and cognitive dissonance

cum assensione cogitare

Cum assensione cogitare, Glauben heisst denkend zustimmen: René Buchholz bringt auf feinschwarz.net einige Gedanken zu Max Horkheimers Hypothese, der Glauben sei eine Erfindung des Protestantismus, um einerseits die Wissenschaft, andererseits den Aberglauben nicht als einzige Alternative zu haben.

Die Unterscheidung des Glaubens vom bloßen Meinen einerseits und Wissen andererseits kennzeichnet indessen nicht erst die Reformation, wie Horkheimer meint, sondern wird bereits in der Scholastik vertreten […]. Nach Augustinus und Thomas bedeutet Glauben „cum assensione cogitare“ […] Der Glaube ist ein Akt des Intellekts […], verbunden mit dem Willen. Er bezieht sich auf eine Autorität, deren Glaubwürdigkeit durchaus geprüft werden darf, die vernünftigen Einsichten nicht widerspricht und Zustimmung verdient; eine Zustimmung, die getragen ist von göttlicher Gnade.

Unbedingt lesen!

Es gibt keine Menschenrassen

Natürlich gibt es keine Menschenrassen, von Rassen spricht man nur noch im Zusammenhang mit der Tierzucht, wo absichtlich bestimmte Gruppeneigenschaften gezüchtet werden.

Trotzdem habe ich ein Problem mit der Jenaer Erklärung (zitiert nach hpd.de)

Aus genetischer Sicht gebe es im Genom des Menschen “keinen einzigen fixierten Unterschied, der zum Beispiel Afrikaner von Nicht-Afrikanern trennt. Es gibt – um es explizit zu sagen – somit nicht nur kein einziges Gen, welches ‘rassische’ Unterschiede begründet, sondern noch nicht mal ein einziges Basenpaar”. Äußere Merkmale, an denen Rassisten ihre Abwertung von bestimmten Menschengruppen festmachen, seien oberflächliche und biologisch leicht wandelbare Anpassungen an geographische Gegebenheiten. Bis vor 8000 Jahren seien die Menschen in Europa noch “stark pigmentiert” gewesen. Erst durch die Einwanderung von Menschen mit hellerer Hautfarbe aus Anatolien und dem damit einsetzenden Beginn der Landwirtschaft habe sich dies geändert, da es sich bei einer stark pflanzenbasierten Kost im dunklen Winter Europas als evolutionärer Vorteil erwies, hellere Haut zu haben und damit genügend Vitamin D produzieren zu können.
“Die helle Hautfarbe der Menschen im nördlichen Europa ist jünger als 5000 Jahre”, hält die Jenaer Erklärung fest. “Die Verknüpfung von Merkmalen wie der Hautfarbe mit Eigenschaften oder gar angeblich genetisch fixierten Persönlichkeitsmerkmalen und Verhaltensweisen, wie sie in der Blütezeit des anthropologischen Rassismus verwendet wurden, ist inzwischen eindeutig widerlegt. Diese Argumentation heute noch als angeblich wissenschaftlich zu verwenden, ist falsch und niederträchtig. Es gibt auch keinen wissenschaftlich nachgewiesenen Zusammenhang zwischen Intelligenz und geographischer Herkunft, aber einen deutlichen mit sozialer Herkunft.”

Die Erklärung hat recht, dass der Rassebegriff eigentlich nur noch von Rassisten verwendet wird.

Es gibt aber durchaus fixierte phänotypische und genetische Unterschiede in geographischen Regionen – also einzelnen Volksgruppen oder Populationen.

M9 ist nach gängiger Forschung der “out of Africa” Marker, siehe Wikipedia

Die Erklärung sagt ja auch, dass Europäer näher verwandt sind mit Ostafrikanern, als Ostafrikaner mit Südafrikanern. Wie sollte eine solche Aussage möglich sein, wenn man keine Marker dafür hätte Für Abstammungstheorien wird oft die Kombination von SNP Marker verwandt. Mit Hilfe der “principal component analysis” wurde zum Beispiel der ursprüngliche afrikanische Stammbaum  im letzten Jahr revidiert.

Quelle und Details auf https://academic.oup.com/hmg/article/27/R2/R209/4993963

“Helle Hautfarbe / bessere Vitamin D Konversion” auch bekannt als Loomis Hypothese  als Triebfeder der Evolution ist genauso strittig. Ohne die Literatur zur Pigmentierung der Haut zu rekapitulieren– der Zweck der Pigmentierung ist eher der Schutz der Basalzellschicht vor UV Strahlung als die Einschränkung der Vitamin D Produktion, die ansonsten auch ohne Pigmentierung selbst limitierend ist.

Es ist auch nicht so, dass dunkle Hautfarbe die ursprüngliche Hautfarbe von H. sapiens in Afrika ist und Europäer mit heller Hautfarbe Mutanten sind. Helle und dunkle Hautfarbe sind wohl eher die Extreme einer ansonsten mittleren Helligkeit. Der letzte Stand steht dabei  in dem Science 2017 Paper von Sarah Tishkoff.

Examining ethnically diverse African genomes, we identify variants in or near SLC24A5, MFSD12, DDB1, TMEM138, OCA2, and HERC2 that are significantly associated with skin pigmentation. … Functional analyses indicate that MFSD12 encodes a lysosomal protein that affects melanogenesis in zebrafish and mice, and that mutations in melanocyte-specific regulatory regions near DDB1/TMEM138 correlate with expression of ultraviolet response genes under selection in Eurasians.

In dieser Liste steht jedenfalls kein Vitamin D – Gen, so dass die Jenaer Erklärung auch hier nicht dem Wissenstand entspricht.

An irreversible experiment

Transgenic Aedes aegypti Mosquitoes Transfer Genes into a Natural Population. Scientific Reportsvolume 9, Article number: 13047 (2019).

In an attempt to control the mosquito-borne diseases yellow fever, dengue, chikungunya, and Zika fevers, a strain of transgenically modified Aedes aegypti mosquitoes containing a dominant lethal gene has been developed by a commercial company, Oxitec Ltd. …. Evidently, rare viable hybrid offspring between the release strain and the Jacobina population are sufficiently robust to be able to reproduce in nature. The release strain was developed using a strain originally from Cuba, then outcrossed to a Mexican population. Thus, Jacobina Ae. aegypti are now a mix of three populations. It is unclear how this may affect disease transmission or affect other efforts to control these dangerous vectors.

More mutations, more asthma?

While some researchers still believe that genetics cannot be responsible for the asthma epidemic as the prevalence increased with only two generations I have no doubt that (within the gene by environment framework) any environmental change is a necessary but not sufficient cause.
I would count also epigenetic changes as “genetic” while there seems now even direct evidence of an increased mutational load in humans

While the overall deleterious homozygosity has consistently decreased, risk alleles have steadily increased in frequency over that period of time. Those that increased most are associated with diseases such as asthma, Crohn disease, diabetes and obesity, which are highly prevalent in present-day populations.

Cognitive bias codex

I am sure, I wrote or talked about it before, but cannot find it.

Maybe all mission critical hypothesis should undergo a bias check?

So here again –  a link to the cognitive bias codex plot of Terry Heick from https://www.teachthought.com (that is itself based on Wikipedia).

People seem to have an astonishing ability to believe their GPS is always right

Having bought a new bussole yesterday, I found this morning a blog entry  “Why Our GPS Devices Can Betray Us

So why is it that our maps — digital or otherwise — so often get us lost? For one thing, they’re usually used for exploring unfamiliar places. Many indigenous navigators, in contrast, practice their skills across large but generally known areas; even if the individual does not have direct experience of a place, they will likely have heard descriptions of it, some of which are passed down generationally. For Westerners, the combination of a lack of local knowledge and unquestioned faith in the power of a map can be disastrous, particularly when we forgo our own perception, instincts, and problem-solving skills. Far from home and familiar reference points, Tom and I followed our GPS’s directions, compounding one bad decision after another, even though we knew Pimlico was south. People seem to have an astonishing ability to believe their GPS is always right, even when such belief defies logic. … “We are largely unconscious of the centrality of maps in contemporary Western life ” [David Turnbull] writes … Turnbull locates the origins of this phenomenon in the cartographic revolution around 1600 in Europe. At that time, maps began to be seen as emblematic of scientific knowledge, and in exchange scientific theories were conceived as maplike.

A compass will always help, even when there is no sun, as we humans have not trained our ability to sense magnetic fields according to some new research.

We report here a strong, specific human brain response to ecologically-relevant rotations of Earth-strength magnetic fields. Following geomagnetic stimulation, a drop in amplitude of electroencephalography (EEG) alpha-oscillations (8–13 Hz) occurred in a repeatable manner. Termed alpha-event-related desynchronization (alpha-ERD), such a response has been associated previously with sensory and cognitive processing of external stimuli including vision, auditory and somatosensory cues.