< 0 Detracted from science

“Research” that detracted from science

The link between scientific value and content is broken at PNAS.org

gettingwell4 < 0 Detracted from science, Neurochemicals, Oxytocin, Telomeres

Should we expect content posted on the Proceedings of the National Academy of Sciences of the United States of America to have scientific value?

This 2016 Singapore study was a “PNAS Direct Submission” that claimed:

“This paper makes a singular contribution to understanding the association between biological aging indexed by leukocyte telomeres length (LTL) and delay discounting measured in an incentivized behavioral economic task.

LTL is an emerging marker of aging at the cellular level, but little is known regarding its link with poor decision making that often entails being overly impatient.”

1. Whether measured at the level of a human or of a blood cell, in 2016 there wasn’t incontrovertible evidence to support:

  • “Biological aging indexed by leukocyte telomeres length
  • LTL is an emerging marker of aging at the cellular level”

Using an epigenetic clock to distinguish cellular aging from senescence found:

“Cellular ageing is distinct from cellular senescence and independent of DNA damage response and telomere length.”

If that study was too recent, the researchers and reviewer knew or should have known of studies such as this 2009 study that found the correlation between a person’s chronological age and blood cell telomere length was r = −0.51 in women and r = −0.55 in men.

2. A study of biological aging in young adults with limited findings was cited for evidence that “the seeds of biological aging are widely thought to be planted early in life.” That study didn’t elucidate the point, however, as it didn’t fully link its measurements of 38-year-old subjects with measurements taken during the subjects’ early lives.

F2.large

3. Problematic research with telomere length was cited for evidence that “other factors, such as the early family environment, lifestyle, and stress, also have considerable impact on cellular aging.” The researchers had to be willing to overlook that study’s multiple questionable practices in order to cite it as evidence for anything.

4. Deliberately overlooking abundant disconfirming evidence, the current study used a one-to-one correspondence of telomere length and cellular aging.

The researchers went on to speciously model a relationship between telomere length and the behavioral trait “poor decision making that often entails being overly impatient.” That overreach was further stretched to the breaking point:

“We then asked if genes possibly modulate the effect of impatient behavior on LTL.

The oxytocin receptor gene (OXTR) polymorphism rs53576, which has figured prominently in investigations of social cognition and psychological resources, and the estrogen receptor β gene (ESR2) polymorphism rs2978381, one of two gonadal sex hormone genes, significantly mitigate the negative effect of impatience on cellular aging in females.”

The “significantly mitigate” finding was “fun with numbers” that produced false effects rather than solid evidence. Consider that:

  1. The study’s model disregarded the probability that “Cellular ageing is independent of telomere length.”
  2. The researchers provided no mechanisms that plausibly linked performance “in an incentivized behavioral economic task” with telomere length.
  3. The researchers didn’t demonstrate any causal mechanisms whereby two gene variants plausibly affected the task performance’s purported effect on telomere length.

What’s the real reason this poor-quality paper’s reviewer forwarded it to PNAS.org?

http://www.pnas.org/content/113/10/2780.full “Delay discounting, genetic sensitivity, and leukocyte telomere length”

A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Neurochemicals, Oxytocin, Stress , , , ,

This 2016 Georgia human study found:

“A role for OXTR [oxytocin receptor gene] in understanding the influence of early environments on adult psychiatric symptoms.

Data on 18 OXTR CpG sites, 44 single nucleotide polymorphisms, childhood abuse, and adult depression and anxiety symptoms were assessed in 393 African American adults. The Childhood Trauma Questionnaire (CTQ), a retrospective self-report inventory, was used to assess physical, sexual, and emotional abuse during childhood.

While OXTR CpG methylation did not serve as a mediator to psychiatric symptoms, we did find that it served as a moderator for abuse and psychiatric symptoms.”

From the Limitations section:

  1. “Additional insight will likely be gained by including a more detailed assessment of abuse timing and type on the development of biological changes and adverse outcomes.
  2. The degree to which methylation remains fixed following sensitive developmental time periods, or continues to change in response to the environment, is still a topic of debate and is not fully known.
  3. Comparability between previous findings and our study is limited given different areas covered.
  4. Our study was limited to utilizing peripheral tissue [blood]. OXTR methylation should ideally be assessed in the tissues that are known to express OXTR and directly involved in psychiatric symptoms. The degree to which methylation of peripheral tissues can be used to study methylation changes in response to the environment or in association with behavioral outcomes is currently a topic of debate.
  5. Our study did not evaluate gene expression and thus cannot explore the role of study CpG sites on regulation and expression.”

Addressing the study’s limitations:

  1. Early-life epigenetic regulation of the oxytocin receptor gene demonstrated – with no hint of abuse – how sensitive an infant’s experience-dependent oxytocin receptor gene DNA methylation was to maternal care. Treating prenatal stress-related disorders with an oxytocin receptor agonist provided evidence for prenatal oxytocin receptor gene epigenetic changes.
  2. No human’s answers to the CTQ, Adverse Childhood Experiences, or other questionnaires will ever be accurate self-reports of their prenatal, infancy, and early childhood experiences. These early development periods were likely when the majority of the subjects’ oxytocin receptor gene DNA methylation took place. The CTQ self-reports were – at best – evidence of experiences at later times and places, distinct from earlier experience-dependent epigenetic changes.
  3. As one example of incomparability, the 2009 Genomic and epigenetic evidence for oxytocin receptor deficiency in autism was cited in the Introduction section and again in the Limitations section item 4. Since that study was sufficiently relevant to be used as a reference twice, the researchers needed to provide a map between its findings and the current study.
  4. Early-life epigenetic regulation of the oxytocin receptor gene answered the question of whether or not an individual’s blood could be used to make inferences about their brain oxytocin receptor gene DNA methylation. The evidence said: NO, it couldn’t.
  5. It’s assumed that oxytocin receptor gene DNA methylation directly impacted gene expression such that increased levels of methylation were associated with decreased gene transcription. The study assumed but didn’t provide evidence that higher levels of methylation indicated decreased ability to use available oxytocin due to decreased receptor expression. The study also had no control group.

To summarize the study’s limitations:

  1. The study zeroed in on childhood abuse, and disregarded evidence for more relevant factors determining an individual’s experience-dependent oxytocin receptor gene DNA methylation. That smelled like an agenda.
  2. The study used CTQ answers as determinants, although what happened during the subjects’ earliest life was likely when the majority of epigenetic changes to the oxytocin receptor gene took place. If links existed between the subjects’ early-life DNA methylation and later-life conditions, they weren’t evidenced by CTQ answers about later life that couldn’t self-report relevant experiences from conception through age three that may have caused DNA methylation.
  3. There was no attempt to make findings comparable with cited studies. That practice and the lack of a control group reminded me of Problematic research with telomere length.
  4. The researchers tortured numbers until they confessed “that CpG methylation may interact with abuse to predict psychiatric symptoms.” But there was no direct evidence that each subject’s blood oxytocin gene receptor DNA methylation interacted as such! Did the “may interact” phrase make the unevidenced inferences more plausible, or permit contrary evidence to be disregarded?
  5. See Testing the null hypothesis of oxytocin’s effects in humans for examples of what happens when researchers compound assumptions and unevidenced inferences.

The study’s institution, Emory University, and one of the study’s authors also conducted Conclusions without evidence regarding emotional memories. That 2015 study similarly disregarded relevant evidence from other research, and made statements that weren’t supported by that study’s evidence.

The current study used “a topic of debate” and other disclaimers to provide cover for unconvincing methods and analyses in pursuit of..what? What overriding goals were achieved? Who did the study really help?

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/cdev.12493/ “Oxytocin Receptor Genetic and Epigenetic Variations: Association With Child Abuse and Adult Psychiatric Symptoms”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Does vasopressin increase mutually beneficial cooperation?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Beliefs, Brain hemispheres, Cerebrum, Hippocampus, Limbic system, Neurochemicals, Oxytocin, Vasopressin

This 2016 German human study found:

“Intranasal administration of arginine vasopressin (AVP), a hormone that regulates mammalian social behaviors such as monogamy and aggression, increases humans’ tendency to engage in mutually beneficial cooperation.

AVP increases humans’ willingness to cooperate. That increase is not due to an increase in the general willingness to bear risks or to altruistically help others.”

One limitation of the study was that the subjects were all males, ages 19-32. The study’s title was “human risky cooperative behavior” while omitting subjects representing the majority of humanity.

Although the researchers claimed brain effects from vasopressin administration, they didn’t provide direct evidence for the internasally administered vasopressin in the subjects’ brains. A similar point was made about studies of vasopressin’s companion neuropeptide, oxytocin, in Testing the null hypothesis of oxytocin’s effects in humans.

A third limitation was that although the researchers correlated brain activity with social behaviors, they didn’t carry out all of the tests necessary to demonstrate the claimed “novel causal evidence for a biological factor underlying cooperation.” Per Confusion may be misinterpreted as altruism and prosocial behavior, the researchers additionally needed to:

“When attempting to measure social behaviors, it is not sufficient to merely record decisions with behavioral consequences and then infer social preferences. One also needs to manipulate these consequences to test whether this affects the behavior.”

http://www.pnas.org/content/113/8/2051.full “Vasopressin increases human risky cooperative behavior”

A problematic study of testosterone’s influence on behavior and brain measurements

gettingwell4 < 0 Detracted from science, Amygdala, Brain development, Cerebrum, Epigenetics, Limbic system, Testosterone , , , , , ,

This 2015 US/Canadian human study of people ages 6 to 22 years found:

“Testosterone-specific associations between amygdala volume and key prefrontal areas involved in emotional regulation and impulse control:

  1. Testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC);
  2. A significant relationship between amygdala-mPFC covariance and levels of aggression; and
  3. Mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression.

These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms.

For the great majority of individuals in this sample, higher thickness of the mPFC was associated with lower aggression levels at a given amygdala volume. This effect diminished greatly and disappeared at more extreme amygdala values.”

The study provided noncausal associations among the effects (behavioral, hormonal, and brain measurements).

From the Limitations section:

“No umbilical cord or amniotic measurements were available in this study and we therefore cannot control for testosterone levels in utero, a period during which significant testosterone-related changes in brain structure are thought to occur.”

There’s evidence that too much testosterone for a female fetus and too little testosterone for a male fetus both have lifelong adverse effects. The researchers dismissed this etiologic line of inquiry with a “supporting the notion” referral to noncausal studies.

The researchers were keen to establish:

“A very specific, aggression-related structural brain phenotype.”

This putative phenotype hinged on:

  • Older subjects’ behavioral self-reports, and
  • Parental assessments of younger subjects’ behavior

exhibited during the previous six months, and within six months of their fMRI scan.

These self-reports and interested-party observations were the entire bases for the “aggressive behavior” and “anxious–depressed” associations! The researchers disingenuously provided multiple references and models for the reliability of these assessments.

Experimental behavioral measurements – such as those done to measure performance in decision studies – may have been more accurate and informative than what the older subjects chose to self-report about their own behavior over the previous six months.

People of all ages have an imperative to NOT be completely honest about their own behavior. One motivation for this condition is that some of our historical realities are too painful to enter our conscious awareness and inform us about our own behavior. As a result, our feelings, thoughts, and behavior are sometimes driven by our histories without us being aware of it.

For example, would a teenager/young adult subject self-report an impulsive act, even if they didn’t fully understand why they acted that way? Maybe they would if the act could be viewed as prosocial, but what if it was antisocial?

What are the chances that the lives of these teenager/young adult subjects were NOT filled with impulsive actions during the six months before their fMRI scans? Could complete and accurate self-reports of such behaviors be expected?

Experimental behavioral measurements may have also been more accurate and informative than second-hand, interested-party observations of the younger subjects. Could a parent who provided half of the genes and who was responsible for many of their child’s epigenetic changes make anything other than subjective observations of their handiwork’s behavior?

Epigenetic studies have shown that adaptations to environments are among the long-lasting causes for effects that include behavior, hormones, and brain measurements. Why, in 2015, did researchers spend public funds developing what they knew or should have known would be noncausal associations, while not investigating possible causes for these effects?

Why weren’t the researchers interested enough to gather and assess etiologic genetic and epigenetic evidence? Was it that difficult to get blood samples at the same time the subjects gave saliva samples, and perform selected genetic and DNA methylation analyses?

What did the study contribute towards advancing science? Who did the study really help?

My judgment: less than nothing; and nobody. The researchers only wasted public funds advancing a meme, giving it an imprimatur of science.

http://www.psyneuen-journal.com/article/S0306-4530%2815%2900924-5/fulltext “A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood”

A problematic study of beliefs and dopamine

gettingwell4 < 0 Detracted from science, Beliefs, Brainstem, Cerebrum, Dopamine, Limbic system, Lower brain, Neurochemicals, Thalamus , ,

This 2015 Virginia Tech human study found:

“Dopamine fluctuations encode an integration of RPEs [reward prediction errors, the difference between actual and expected outcomes] with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been.

How dopamine fluctuations combine the actual and counterfactual is unknown.”

From the study’s news coverage:

“The idea that “what could have been” is part of how people evaluate actual outcomes is not new. But no one expected that dopamine would be doing the job of combining this information in the human brain.”

Some caveats applied:

  • Measurements of dopamine were taken only from basal ganglia areas. These may not act the same as dopamine processes in other brain and nervous system areas.
  • The number of subjects was small (17), they all had Parkinson’s disease, and the experiment’s electrodes accompanied deep brain stimulation implantations.
  • Because there was no control group, findings of a study performed on a sample of people who all had dysfunctional brains and who were all being treated for neurodegenerative disease may not apply to a population of people who weren’t similarly afflicted.

The researchers didn’t provide evidence for the Significance section statement:

“The observed compositional encoding of “actual” and “possible” is consistent with how one should “feel” and may be one example of how the human brain translates computations over experience to embodied states of subjective feeling.”

The subjects weren’t asked for corroborating evidence about their feelings. Evidence for “embodied states of subjective feeling” wasn’t otherwise measured in studied brain areas. The primary argument for “embodied states of subjective feeling” was the second paragraph of the Discussion section where the researchers talked about their model and how they thought it incorporated what people should feel.

The study’s experimental evidence didn’t support the researchers’ assertion – allowed by the reviewer – that the study demonstrated something about “states of subjective feeling.” That the model inferred such “findings” along with the researchers’ statement that it “is consistent with how one should “feel” reminded me of a warning in The function of the dorsal ACC is to monitor pain in survival contexts:

“The more general message you should take away from this is that it’s probably a bad idea to infer any particular process on the basis of observed activity.”

The same researcher who hyped An agenda-driven study on beliefs, smoking and addiction that found nothing of substance was back again with statements such as:

“These precise, real-time measurements of dopamine-encoded events in the living human brain will help us understand the mechanisms of decision-making in health and disease.”

It’s likely that repeated hubris is one way researchers respond to their own history and feelings, such as their need to feel important as mentioned on my Welcome page.

The Parkinson’s patients were willing to become lab rats with extra electrodes that accompanied brain implantations to relieve their symptoms. Findings based on their playing a stock market game didn’t inform us about “mechanisms of decision-making in health and disease” in unafflicted humans. As one counter example, what evidence did the study provide that’s relevant to healthy humans’ decisions to remain healthy by taking actions to prevent disease?

The unwarranted extrapolations revealed a belief that the goal of research should be to explain human actions by explaining the actions of molecules. One problem caused by the preconceptions of this widespread belief is that it leads to study designs and models that omit relevant etiologic evidence embedded in each of the subjects’ historical experiences.

This belief may have factored into why the subjects weren’t asked about their feelings. Why didn’t the study’s design consider as relevant subject-provided evidence for feelings? Because the model already contrived explanations for feelings underlying the subjects’ actions.

http://www.pnas.org/content/113/1/200.full “Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward”

It is known: Are a study’s agendas more important than its evidence?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Brain hemispheres, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2015 Swiss human study’s Abstract began:

“It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling.”

The study had several statements that were unconvincingly supported by the study’s findings. One such statement in the Conclusions section was:

“This study supports the view that early-life adversity may induce long-lasting epigenetic changes in stress-related genes, thus offering clues as to how intergenerational transmission of anxiety and trauma could occur.”

However, the study’s evidence for “intergenerational transmission of anxiety and trauma” as summarized in the Limitations section was:

“This study did not directly associate child behavior or biology to maternal behavior and biology.”

In another example, the Discussion section began with:

“The severity of maternal anxiety was significantly correlated with mean overall methylation of 4 CpG sites located in exon IV of the BDNF promoter region as measured from DNA extracted from mothers’ saliva.

In addition, methylation at CpG3 was also significantly associated with maternal exposure to domestic violence during childhood, suggesting that BDNF gene methylation levels are modulated by early adverse experiences.”

The researchers assessed five DNA methylation values (four individual sites and the overall average). The CpG3 site was “significantly associated with maternal exposure to domestic violence during childhood” and the three other CpG sites’ methylation values were not.

IAW, the researchers found only one of four sites’ methylation values significantly associated to only one of many studied early adverse experiences. This finding didn’t provide sufficient evidence to support the overarching statement:

“BDNF gene methylation levels are modulated by early adverse experiences.”

To make such a generally applicable statement – more than one BDNF gene’s methylation levels could be directly altered by more than one early adverse experience – the researchers would, AT A MINIMUM, need to provide evidence that:

  1. The one category of significantly associated early adverse experience directly altered the one significantly associated CpG site’s DNA methylation level
  2. Other categories of early adverse experiences were fairly represented by the one significantly associated experience category
  3. Other categories of early adverse experiences could directly alter other BDNF genes’ DNA methylation levels
  4. The significantly associated DNA methylation level of only one out of four CpG sites was fairly represented by the overall average of the four sites
  5. Other BDNF gene’s methylation levels were fairly represented by the overall average of the four sites

If researchers and sponsors must have agendas, a worthwhile, evidence-supported one would be to investigate prenatal and perinatal epigenetic causes for later-life adverse effects.

As Grokking an Adverse Childhood Experiences (ACE) score pointed out, environmental factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.

What’s the downside of conducting studies that may “directly associate child behavior or biology to maternal behavior and biology” during time periods when a child’s environment has the greatest impact on their development?

When prenatal and perinatal periods aren’t addressed, researchers and sponsors neglect the times during which many harmful epigenetic consequences may be prevented. It is known.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143427 “BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample”

Where do our beliefs about our children come from? An autism example

gettingwell4 < 0 Detracted from science, Beliefs, Brain development, Cerebrum, Epigenetics, Glutamate, Limbic system, Neurochemicals, Primal Therapy , , , ,

A 2015 case study by Ohio physicians highlighted:

“Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms.

These symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians.

The case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction.”

I was somewhat taken aback by the Abstract and Introduction statements:

“All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized.

This form of ASD is known to be heritable, as are all forms of ASD, despite the previous belief to the contrary, though the mechanisms of inheritance, both genetic and epigenetic, are not well characterized.”

The definition of heritable as used was “able to be passed from parent to child before birth.” The reference provided was a 2014 French review Gene × Environment Interactions in Autism Spectrum Disorders: Role of Epigenetic Mechanisms.

I didn’t see the “known to be heritable” phrase mentioned in the referenced review. However, I also didn’t see anything stated in the review or cited from its 217 references that disproved this phrase.

I shouldn’t have been surprised by “despite the previous belief to the contrary” in the above quotation. I’d guess that the physicians frequently encountered parents who needed such beliefs when faced with their child’s condition.

A relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is: a major function that our cerebrums have evolutionarily adapted is to use ideas and beliefs to repress pain and make us more comfortable.

I value this inference as an empathetic method of interpreting people’s behaviors and expressions of thoughts and feelings.

When a “known to be heritable” phrase can unleash pain, it likely won’t be understood in its appropriate context. Among the physicians’ challenges was a barrier that kept the parent’s pain from being felt – the belief.

http://innovationscns.com/autism-in-the-son-of-a-woman-with-mitochondrial-myopathy-and-dysautonomia-a-case-report/ “Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report”

2023 update – After all the medical gaslighting on display this decade, I don’t what it would take for me to trust a medical professional anymore. These doctors ‘knew’ somehow that autism was heritable, yet couldn’t describe mechanisms of inheritance? Please. Why were medical professionals trusted in the first place?

A problematic study of DNA methylation in frontal cortex development and schizophrenia

gettingwell4 < 0 Detracted from science, Amygdala, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Lower brain , , , , , ,

This 2015 Baltimore human study found:

“CpGs that differ between schizophrenia patients and controls that were enriched for genes related to development and neurodifferentiation.

The schizophrenia-associated CpGs strongly correlate with changes related to the prenatal-postnatal transition and show slight enrichment for GWAS [genome-wide association study] risk loci while not corresponding to CpGs differentiating adolescence from later adult life.

Only a fraction of the illness-associated CpGs, 4.6%, showed association to nearby genetic variants in the meQTL [methylation quantitative trait loci] analysis, further suggesting that these findings may be more related to the epiphenomena of the illness state than to the genetic causes of the disorder.

These data implicate an epigenetic component to the developmental origins of this disorder.”

It wasn’t surprising in 2015 to find “an epigenetic component to the developmental origins of this disorder.” From the supplementary material:

“Diverse chromatin states suggest vastly different epigenetic landscapes of the prenatal versus postnatal human brain.

Approximately half of the CpGs had DNAm [DNA methylation] levels positively correlated with expression across the lifespan, and half had DNAm levels negatively correlated.

These results suggest that many of the epigenetic changes occurring between prenatal and postnatal life in prefrontal cortex manifest in the transcriptome, and that the directionality of association is not strictly linked to the location of the CpG or DMR [differentially methylated region] with respect to an annotated gene.

Diagnosis-associated CpGs were relatively small compared with those differentially methylated between fetal and postnatal samples.”

The studied brain area was limited to the dorsolateral portion of the prefrontal cortex, which isn’t mature in humans until we’re in our late teens/early twenties.

The researchers ignored brain areas that were fully developed or further along in development – such as the limbic system – during “the prenatal-postnatal transition.”

The researchers intentionally blinded themselves from discovering “many of the epigenetic changes occurring between prenatal and postnatal life” possibly associated with schizophrenia and these more-developed brain areas.

Where’s the evidence that the developmental origins of schizophrenia have no associations with brain structures whose development closely approximates their lifelong functionalities at birth?

The study’s limitations didn’t hamper researcher hubris in a press release for a site that touts business news, such as:

“This conclusion, while perhaps not the final verdict on the subject, is hard to resist given this remarkable evidence”

Did the spokesperson really understand GWAS? Or was he trying to exploit public ignorance of GWAS?

There’s a scientist’s view of GWAS at What do GWAS signals mean? that better puts this study’s findings into perspective. When understanding GWAS at an individual level, it should also be acknowledged that Genetic statistics don’t necessarily predict the effects of an individual’s genes.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4181.html “Mapping DNA methylation across development, genotype and schizophrenia in the human frontal cortex” (not freely available). Use the full study link from the above-mentioned press release.

Is the purpose of research to define opportunities for interventions?

gettingwell4 < 0 Detracted from science, Brain development, Epigenetics, Primal Therapy, Stress , , , , , , , , ,

In this 2014 review, a social scientist first presented an interpretive history of what he found to be important in the emergence of epigenetics. He proceeded into his ideas of “a possible agenda of the social studies of the life-sciences” in the “postgenomic age” with headings such as “Postgenomic biopolitics: “upgrade yourself” or born damaged for ever?”

This perspective included:

“The upgradable epigenome may become the basis for a new motivation to intervene, control and improve it through pharmacological agents or social interventions.

An important trend is the use of epigenetic and developmental findings in the so-called early-intervention programmes.

It is possible that epigenetic findings will become increasingly relevant in social policy strategies.”

In this blog I often highlight research that may help us understand details of how each of us is a unique individual. It’s my view that insofar as research helps each of us understand our unique, real self, we may be able to empathetically understand others’ unique qualities.

Click individual differences for a sample of how researchers explain away uniqueness in order to converge on a study’s desired objectives. There’s seldom an attempt to further understand what caused each subject to develop their unique qualities.

Why would this reviewer advocate that

  • Researchers,
  • People working in the social sciences,
  • People employed or involved in social services, and
  • Their sponsors and employers

intentionally disregard another individual’s unique qualities?

I’ll answer this question from a perspective that explains how this common, reflexive action derives from a person being unable to face the facts of their own life. Pertinent fundamentals of Dr Arthur Janov’s Primal Therapy are:

  1. Pain motivates a person’s unconscious act-outs of their underlying problems.
  2. The behavior that caused a problem is sometimes also the act-out behavior.
  3. Act-outs enable a person to re-experience the feelings of their historical struggles, in a vain attempt to resolve them.
  4. Due to pain barriers, people seldom become consciously aware of and – more importantly – address the causes for their own problematic behavior.
  5. “The patient has the power to heal himself.”

A consequent hypothesis is that a person will often glorify their unconscious act-outs and surround themself with justifications for these actions. For example, a person who can’t sit still may refer to their incessant activity with socially acceptable phrases such as “I’m always busy” or “I love to travel.” They’ll structure their life to enable their unconscious behavior, never questioning how they were attracted to an always-on-the-go occupation such as flight attendant, only vaguely feeling that they were made for it.

The behavior relevant to the current review may be exhibited by a person with a history of having no control over their own life. Following the above first two fundamentals, the pain of historically not having control over their life may motivate them to control other people’s lives.

Unfortunately for everyone who’s affected, such unconscious act-outs don’t resolve anything:

  1. The initiator may achieve some symbolic satisfaction by controlling others’ lives.
  2. This temporary satisfaction doesn’t make the initiator’s underlying problems less painful.
  3. The motivation impelling these unconscious act-outs isn’t thereby reduced.
  4. So the initiator soon repeats their controlling behavior, stuck in a loop of unresolved feelings.
  5. Since the self-chosen interests of someone who’s being controlled are lesser concerns to the initiator than exercising control, the controlled person may or may not be helped by the controller’s act-outs.

Research provides abundant evidence that we are unique individuals.

This is a strong indicator of who is best qualified to direct each of our unique lives.

A person who is driven to control others’ lives won’t accept epigenetic research as instructive for understanding, honoring, and respecting others as unique individuals. They’ll use research as a way to enable their own unconscious act-outs, and view it as offering opportunities for interventions into the lives of others.

This is the way that “pharmacological agents or social interventions” are often the intended “use of epigenetic and developmental findings.” Interventions receive justifications with “a possible agenda of the social studies of the life-sciences.”

Becoming aware of one’s own act-outs – and then individually addressing one’s own underlying problems – often take backseats to employment and other concerns to keep enabling one’s own behavior. That makes it likely that interventions justified by “epigenetic findings..in social policy” will continue, whether or not the subjects agree that they’re being helped.

For examples, take a look at a few of the YouTube presentations by people employed in the social sciences and social services on a topic of epigenetics. Compare them with the current state of epigenetic research in Grokking an Adverse Childhood Experiences (ACE) score.

What did you notice? How many presentations emphasized disrupted prenatal development – a period when problems can be prevented? Did you instead see that many more of the presentations emphasized controlling behavior?

http://journal.frontiersin.org/article/10.3389/fnhum.2014.00309/full “The social brain meets the reactive genome: neuroscience, epigenetics and the new social biology“

Conclusions without evidence regarding emotional memories

gettingwell4 < 0 Detracted from science, Amygdala, Cerebrum, Hippocampus, Limbic system, Memory

The last sentence in the Significance section of this 2015 Emory/Harvard rodent study was:

“These data highlight the potential to exploit sensory system plasticity as a means of ameliorating negative emotional memories that may be tied to peripheral sensory systems.”

The “ameliorating negative emotional memories” part of this statement was incongruent with what the study actually found, as summarized by the Abstract’s last sentence:

“These data suggest that learning-induced freezing behavior, structural alterations, and enhanced neural sensory representation can be reversed in adult mice following extinction training.”

The study performed fear extinction experiments. The researchers and reviewer knew or should have known about prior studies such as Fear extinction is the learned inhibition of retrieval of previously acquired responses whose findings demonstrated that fear extinction doesn’t depend on memory retrieval.

Based on the previous research, the subjects’ “negative emotional memories” possibly weren’t affected at all by the current study’s extinction experiments!

The researchers provided neither direct evidence for “ameliorating negative emotional memories” nor studied areas of the subjects’ brains that contained or processed emotional memories, such as the hippocampus, amygdala, and prefrontal cortex. But – after all – Harvard.

What purposes did it serve for the researchers to make a Significance statement about “ameliorating negative emotional memories” when this wasn’t supported by the study’s findings? What part did the reviewer play in approving this statement?

Where was the study’s evidence to support the headline and statements in the news release such as:

“New Study Indicates That Sense of Smell Could Play Major Role in New Approaches to Treating PTSD

It’s possible for fear behaviors associated with emotional learning to be reversed through exposure-based talk therapy.”

Could this rodent study’s olfactory system findings be properly extrapolated to human talk therapy?

NO! But – Harvard.

http://www.pnas.org/content/112/41/12846.full “Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size”

A study of how “age” itself wasn’t a causal factor for wound-healing differences

gettingwell4 < 0 Detracted from science, Stress

This 2015 California rodent study found:

“A surprising beneficial effect of mitochondrial dysfunction at young age (accelerated wound closure), and a potential mechanism for the reduced epidermal regeneration at older ages (stem cell depletion).”

The researchers generated mitochondrial oxidative stress by deleting:

“A nuclear gene that encodes the mitochondrial antioxidant enzyme superoxide dismutase 2 (Sod2). Epidermal Sod2 loss induced cellular senescence, which irreversibly arrested proliferation in a fraction of keratinocytes.

Surprisingly, in young mice, Sod2 deficiency accelerated wound closure, increasing epidermal differentiation and reepithelialization, despite the reduced proliferation.

In contrast, at older ages, Sod2 deficiency delayed wound closure and reduced epidermal thickness, accompanied by epidermal stem cell exhaustion.”

The term “cellular senescence” used above is defined as: a cell can no longer replicate. Although the word “senescence” implies that chronological age is a factor, “cellular senescence” by definition isn’t about age.

This study’s etiologic findings weren’t “age” itself, but:

  1. Sod2 deficiency – the subjects’ genetic condition – which increased free radicals;
  2. The interplay of Sod2 deficiency with varying keratinocyte and epidermal stem cell levels; and
  3. Sod2 deficiency’s influence on other items shown in the supplementary material, to include varying “mRNA levels of wound healing-related growth factors.”

I guess the “age was the cause” meme is hard to stop repeating, though. The researchers said they could “identify a previously unidentified age-dependent role for mitochondria in quality and wound closure,” and repeated the “age-dependent” phrase in the study title.

Is pitching this meme an organizational imperative for the Buck Institute for Research on Aging, no matter what their researchers find?

http://www.pnas.org/content/112/33/10407.full “Pleiotropic age-dependent effects of mitochondrial dysfunction on epidermal stem cells”

What’s an appropriate control group for a schizophrenia study?

gettingwell4 < 0 Detracted from science, Cerebrum ,

The researchers who did Our long-term memory usually selects what we pay closer visual attention to study were back zapping subjects’ brains again in this 2015 human study.

Prior to zapping subjects’ brains:

“In healthy individuals, these theta waves were steady and synchronized, but in people with schizophrenia, the waves were weak and disorganized, suggesting that they were having a harder time processing the mistake. And the subjects’ behavior bore that out—the healthy subjects slowed down by a few milliseconds when they made mistakes and did better in the next round, while the subjects with schizophrenia did not.”

Processing of an appropriate control group wasn’t clear to me from reading supplementary material. Subject patients were diagnosed with schizophrenia and took psychoactive medication which these researchers equated to chlorpromazine (Thorazine) dosages. Control group subjects had neither the condition nor were prescribed medications.

  • How did these researchers differentiate influences of psychoactive medications on experimental results from other influences on subjects’ conditions?
  • Were there numerical calculations not shown in supplementary material that somehow nullified effects of psychoactive medications?
  • To be sure that zapping was effective for subjects’ conditions, wouldn’t control group subjects need to take the same medications so that experimental data reflected only differences attributable to schizophrenia?

These researchers also asserted:

“Causal changes in the low-frequency oscillations improved behavioral responses to errors and long-range connectivity at the single-trial level.”

However, brain waves can’t be termed as base causes of human behavior. Studies such as:

clearly established that brain waves are effects of base causes.

http://www.pnas.org/content/112/30/9448.full “Synchronizing theta oscillations with direct-current stimulation strengthens adaptive control in the human brain”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Using epigenetic DNA methylation markers to estimate biological age

gettingwell4 < 0 Detracted from science, Epigenetics, Stress, Telomeres

I curated this 2015 Georgia human study only for its use of two methods of estimating biological age. The researchers misguidedly used these techniques to help paint a scientific patina on an agenda.

One of the methods was originated by a coauthor of The degree of epigenetic DNA methylation may be used as a proxy to measure biological age study. He compared his epigenetic clock technique with the other technique here:

  • His technique used the same 353 DNA regions (CpGs, cytosine and guanine separated by only one phosphate link) across different tissues to compare tissue/organ ages;

  • “The DNA methylation levels of 193 of these markers increase with age but the remaining 160 markers show the opposite behavior.”

  • His technique had a Pearson correlation coefficient of r=0.96 with chronological age in this 2013 study;
  • The other technique:

    “Works poorly for blood samples from subjects who are younger than 20.”

That such methods were available calls into question why the researchers of A study of biological aging in young adults with limited findings didn’t avail themselves of these techniques. They used techniques that were less informative such as telomere length. As an example of how that study’s methods were known to be limited, this 2009 study found that the correlation between chronological age and telomere length was r = −0.51 in women and r = −0.55 in men.

http://www.pnas.org/content/112/33/10325.full “Self-control forecasts better psychosocial outcomes but faster epigenetic aging in low-SES youth”

Do scientists have to perpetuate memes in order to keep their jobs?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Beliefs, Cerebrum, Hippocampus, Limbic system, Thalamus , , ,

I was disgusted by this 2015 Korean human study.

Is the current state of science such that researchers won’t be funded unless there’s an implicit guarantee that their studies will produce politically correct findings? It seemed that the primary reason for the study’s main finding of:

“Neural markers reflecting individual differences in human prosociality”

was to perpetuate that non-causal, non-explanatory meme.

Per If research treats “Preexisting individual differences” as a black box, how can it find causes for stress and depression? it wasn’t sufficient in 2015 to pretend that there are no early-life causes for the observed behavior and fMRI scan results of the subjects. Such a pretense leads to the follow-on pretense that later-life consequences are not effects, but are instead, a “mystery” due to “individual differences.”

The researchers asserted:

“Our present findings shed some light on the mystery of human altruism.”

Weren’t the findings of the People who donated a kidney to a stranger have a larger amygdala 2014 study of extraordinary altruists big enough clues for these researchers to feature the amygdala in the fMRI scans?

The main experiment had the female, college student, right-handed subjects try to “reduce the duration of exposure to stressful noise.” Why weren’t brain areas that are especially susceptible to stress like the hippocampus featured in the fMRI scans?

The secondary reason for the study seemed to be to perpetuate the harmful “self-sacrifice = good, individuality = bad” meme.

The main reason this meme is harmful is that it condones a subset of people’s unconscious act outs. People are encouraged to avoid conscious awareness both of who they really are and of what drives their feelings, thoughts, and actions.

Despite not asking the subjects directly about either their motivations or their histories, these researchers asserted that the study demonstrated:

“The automatic and intuitive nature of prosocial motivation.”

What was largely observed were the subjects’ unconscious act outs, not some higher-order functions as the researchers mischaracterized them.

Similar to Who benefits when research promotes a meme of self-sacrifice? I suspect that a major motivation behind scientific justification for memes like the self-sacrifice promoted by this study is to rush people past what really happened in their lives.

I wonder what value we would place on the “social norms internalized within an individual” if we felt and honestly understood our real history.

This study and the Do you know a stranger’s emotional motivations for smiling? study had the same reviewer, and shared several of the burden-of-proof problems. Both studies demonstrated a lack of researcher interest in finding causes for the observed effects.

What was the agenda with these researchers and the reviewer? Why would the researchers glorify factors that cause difficulties when one tries to live a life of one’s own choosing?

http://www.pnas.org/content/112/25/7851.full “Spatial gradient in value representation along the medial prefrontal cortex reflects individual differences in prosociality”

Running a marathon, cortisol, depression, causes, effects, and agendas

gettingwell4 < 0 Detracted from science, Cerebrum, Cortisol, Limbic system, Lower brain, Memory, Neurochemicals, Stress , ,

Let’s imagine that you decide you want to run a marathon. You haven’t run in six months, and you know you’ll have to train.

On the first day of training, as you run your first mile a friend pops out of nowhere and says, “You’re sweating! That means you’re going up to Mile 14 today! Good job, you’re on your way!”

You may appreciate the encouragement, but would a friend’s assessment have anything to do with your physical reality? Before you’ve run one mile, can an observer of your sweat say with certainty that you’ll run 14 miles on your first day of training?

Yeah. That’s how I felt when reading this 2014 UK study that found:

“Adolescent boys who have high levels of stress hormone ‘cortisol’ along with some symptoms of depression are at a 14 times higher risk of the condition than their peers.”

The researchers latched onto teenagers (12-16 years old, mean 13.7) to assess a psychiatric condition. They stated that a physical effect as common as visible sweat was a biomarker that predicted where some of the teenagers were going with their lives.

The study’s only physical measurements were cortisol from saliva samples at 8:00 a.m. on four consecutive days, then repeated a year later. For comparison, a standard lab test is to measure cortisol from saliva taken four times in one day at 9:00 a.m., 1:00 p.m., 5:00 p.m., and 9:00 p.m.

Cortisol is an effect of multiple potential causes, including stress, which itself is often an effect of multiple potential causes. One common cause of stress and its cortisol byproduct is diet, for example, when a person consumes caffeine.

“Mean time between waking and morning-cortisol collection was 50 min.”

I found it hard to believe that teenagers who:

  • woke up at 7:10 a.m.,
  • gulped down who knows what for breakfast,
  • got ready for, and then
  • went to school for an 8:00 a.m. cortisol test

wouldn’t have relatively “elevated morning cortisol” from the resultant stress.

Subjects self-reported depressive symptoms via a 33-item questionnaire initially and again every four months. They were interviewed for psychiatric diagnoses.

The largest separator used for stratification within subjects was an autobiographic memory test. Without this test, the study wouldn’t have made its main finding, so let’s look at the test’s details:

“Anxious and depressed adolescent patients report significantly elevated levels of over-general categoric memories compared with well controls. Six positive and six negative words are presented on flashcards in pseudorandom order, and participants are instructed to recall a particular memory of an event in their life after each word. Sixty seconds were allowed for each response.

Responses were categorized as specific if they referred to an event with a specific time and place, lasting no longer than 1 d[ay]. Responses were considered overgeneral if they formed a general class of repeated events.”

We can see that the autobiographical memory test only considered the subjects’ verbal expressions – within a short time period – of their recalls of emotionally triggered memories. As informed by the principles described in Agenda-driven research on emotional memories, the recall of an emotional memory is a product of the cerebrum responding to input from limbic system and lower brain areas. When someone describes their recall of an emotionally triggered memory, it’s yet another level further removed from the brain areas that store emotional memories.

We can also see that test scores of the subjects’ verbal expressions aren’t capable of providing any etiologic evidence for an effect of high cortisol. A correlation is the best that could ever be shown by an autobiographic memory test. Again, the study’s main finding hinged on this third-order observational method of trying to figure out what’s going on inside subjects’ brains.

The researchers developed a control group, and made only a token attempt to trace the control group teenagers’ histories:

“The primary caregiver was interviewed about the quality of the family environment in three epochs (0–5, 6–11, and 12–14 y of age).

Four classes were found: optimal class, aberrant parenting, discordant, and hazardous.”

Were we supposed to believe that any primary caregiver would tell the truth about anything in a teenager’s history that indicated they had damaged their child? Good luck with that.

Anyway, the researchers didn’t act as though teenagers’ histories had any significant relationships with any present or future conditions. Their ahistoric biases showed by subsequently processing the entire history of each of the control group teenagers into a 1 or a 0 for the model.

The researchers then modeled this binary assessment to be relevant to the study’s main subjects!

The researchers’ agenda led to predetermined findings. Was the reviewer onboard with this agenda?

  • By disregarding the main subjects’ histories, it couldn’t provide etiologic evidence for any present or future effects.
  • By measuring only early morning cortisol, are we surprised that model numbers could be processed into some correlation?
  • Comparing this sole measurement to 325 measurements taken of subjects in Assessing a mountain climber’s condition without noticing their empty backpack made me wonder about the study designers’ real intentions.

News coverage of the study jumped on its flimsy finding to demand that something must be done. What did researchers offer teenagers who needed help?

  • After citing research that:

    “Showed null effects for two active treatments [cognitive behavioral therapy (CBT) and attentional training, respectively]”

    they recommended some unspecific:

    “New models of public mental health education and intervention in the youth population.”

  • After citing research that found:

    “Current diagnostic classifications [e.g., the Diagnostic and Statistical Manual for Mental Disorders (DSM) and the International Classification of Diseases (ICD)] have proved to have low diagnostic validity for investigations on the etiology, prevention, or treatment of MD [major depression]“

    the study relied on these diagnoses anyway, and then disclaimed:

    “It may also be the case that current classifications, as used in this study, such as DSM and ICD are simply not optimally specified.”

They didn’t make their case that “elevated morning cortisol” effect was an adequate biomarker for teenagers who needed help. They did a disservice to their subjects by neither investigating nor providing any etiologic evidence for observed effects.

Who really benefited from this underlying agenda? I didn’t see that it was teenagers who may have actually needed assistance.

Did the study’s funders know that these efforts had enormous lacks? And what did:

“New models of public mental health education and intervention in the youth population”

really mean?

http://www.pnas.org/content/111/9/3638.full “Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms”