Disproving the cholesterol paradigm

This 2018 review presented evidence that:

“For half a century, a high level of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) has been considered to be the major cause of atherosclerosis and cardiovascular disease (CVD), and statin treatment has been widely promoted for cardiovascular prevention. However, there is an increasing understanding that the mechanisms are more complicated and that statin treatment, in particular when used as primary prevention, is of doubtful benefit.

The authors of three large reviews recently published by statin advocates have attempted to validate the current dogma. This article delineates the serious errors in these three reviews as well as other obvious falsifications of the cholesterol hypothesis.

Our search for falsifications of the cholesterol hypothesis confirms that it is unable to satisfy any of the Bradford Hill criteria for causality and that the conclusions of the authors of the three reviews are based on:

  • Misleading statistics,
  • Exclusion of unsuccessful trials and by
  • Ignoring numerous contradictory observations.

The association between the absolute risk reduction of total mortality in 26 statin trials [squares] included in the study by Silverman et al. and in 11 ignored trials [triangles] and the year where the trial protocols were published. The vertical line indicates the year where the new trial regulations were introduced.

In 2004–2005, health authorities in Europe and the United States introduced New Clinical Trial Regulations, which specified that all trial data had to be made public. Since 2005, claims of benefit from statin trials have virtually disappeared.

This paradigm was proven wrong eighty years ago! How much longer will its harmful consequences continue?

https://www.tandfonline.com/doi/full/10.1080/17512433.2018.1519391 “LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature”


An hour of the epigenetic clock

This 2018 presentation by the founder of the epigenetic clock method described the state of the art up through July 2018. The webinar was given on the release day of The epigenetic clock now includes skin study.

Segments before the half-hour mark provide an introduction to the method and several details about the concurrently-released study. The Q&A section starts a little before the hour mark.

Stuck in the wrong paradigm

This 2019 article questioned the paradigm of determining substance carcinogenicity:

“In the absence of robust epidemiological data, the final arbiter of whether a chemical is considered to be a carcinogen or not has been based on the outcome of long-term rodent bioassays. This approach is incompatible with the current knowledge of the etiology of cancer. The current view of the etiology of cancer suggests that it is not useful to consider carcinogenicity as a single hazardous property with its own hazard category.

There is no bright line between carcinogens and non-carcinogens but rather there is a continuum with some chemicals having high potential, some having no potential, and others having potential at a point along the continuum. This continuum exists alongside other adverse effects. One problem is being stuck in the old practice of wishing to reproduce the binary “carcinogen/non-carcinogen” results of the long-term bioassay rather than move to a new paradigm in assessing the chemical’s position on the spectrum of carcinogenic potential.

The two-year bioassay has such high variability (because of the variability of the carcinogenic process it is trying to measure and the interplay between dose limiting toxicity and cell proliferation inducing toxicity) that the outcome of the assay for compounds with low to intermediate carcinogenic potential is little more than a lottery. After half a century, it has only been used to evaluate less than 5% of chemicals that are in use. It is not reproducible because of the probabalistic nature of the process it is evaluating combined with dose limiting toxicity, dose selection, and study design.”

Unscientific research paradigms will eventually collapse because they can’t withstand the scrutiny of the scientific method. Too bad the coauthors didn’t kill off this one while they were still in positions at the U.S. Environmental Protection Agency, World Health Organization, etc.

https://www.sciencedirect.com/science/article/pii/S0273230019300248 “Chemical carcinogenicity revisited 2: Current knowledge of carcinogenesis shows that categorization as a carcinogen or non-carcinogen is not scientifically credible” (not freely available)

Burying human transgenerational epigenetic evidence

The poor substitutes for evidence in this 2018 US study guaranteed that human transgenerational epigenetically inherited effects wouldn’t be found in the generations that followed after prenatal diethylstilbestrol (DES) exposure:

“A synthetic, nonsteroidal estrogen, DES was administered to pregnant women under the mistaken belief it would reduce pregnancy complications and losses. From the late 1930s through the early 1970s, DES was given to nearly two million pregnant women in the US alone.

Use of DES in pregnancy was discontinued after a seminal report showed a strong association with vaginal clear cell adenocarcinoma in prenatally exposed women. A recent analysis of the US National Cancer Institute (NCI) DES Combined Cohort Follow-up Study showed elevated relative risks of twelve adverse health outcomes.

We do not have sufficient data concerning the indication for DES in the grandmother to determine whether adverse pregnancy outcomes in the third generation might resemble those of their grandmothers. Fourth generation effects of prenatal exposures in humans have not been reported.”

This study had many elements in common with its wretched cited reference [25] “Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine” which is freely available at https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.12136.

That study’s Methods section showed:

  1. Its non-statistical data was almost all unverified self-reports by a self-selected sample of the F2 grandchildren, average age 37.
  2. No detailed physical measurements or samples were taken of the F2 grandchildren, or of their F1 parents, or of their F0 grandparents, all of which are required as baselines for any transgenerational epigenetic inheritance findings.
  3. No detailed physical measurements or samples were taken of their F3 children, which is the generation that may provide transgenerational evidence if the previous generations also have detailed physical baselines.

That study’s researchers drew enough participants (360) such that their statistics package allowed them to impute and assume into existence a LOT of data. But the scientific method constrained them to make factual statements of what the evidence actually showed. They admitted:

“In conclusion, we did not find a transgenerational effect of prenatal famine exposure on the health of grandchildren in this study.”

The current study similarly used the faulty methods 1-3 above to produce results such as:

“We do not have sufficient data concerning the indication for DES in the [F0] grandmother to determine whether adverse pregnancy outcomes in the [F2] third generation might resemble those of their grandmothers. [F3] Fourth generation effects of prenatal exposures in humans have not been reported.”

What did these researchers expect from a study design that permitted non-evidence like educational level?

Human studies of possible intergenerational and transgenerational epigenetic inheritance are urgently needed. There will be abundant evidence to discover if researchers will take their fields seriously.

https://www.sciencedirect.com/science/article/pii/S0890623818304684 “Reproductive and Hormone-Related Outcomes in Women whose Mothers were Exposed in utero to Diethylstilbestrol (DES): A Report from the US National Cancer Institute DES Third Generation Study” (not freely available)

The arrogance of a paradigm exceeding its evidence

This 2018 commentary from the American College of Emergency Physicians by 7 physicians discussed the harm that will result from imposing a mandatory paradigm of sepsis treatment. I’ll quote sections that mention evidence:

“These metrics [for pneumonia treatment] had little evidentiary basis but led to an institutional-fostered culture of overdiagnosis and overtreatment. Have we learned from this folly or does a new sepsis guideline promote similar time-based treatment strategies with little direct supporting evidence?

Like the pneumonia quality measure, this resource-heavy care flows from an overreaching interpretation of evidence. Despite that evidence consistently fails to find a benefit of a single treatment strategy, the Surviving Sepsis Campaign continues to promote recommendations that bypass the individual clinician’s judgment.

Although well intentioned, the current sepsis bundles and the potential penalties associated with noncompliance lay a heavy weight on ED [emergency department] care absent evidence that a net benefit will follow. The proposed Surviving Sepsis Campaign abbreviated bundle heightens the burden by further restricting the time allotted for the identification and treatment of patients with suspected sepsis, all without any evidence of benefit or knowledge of the logistic consequences or cost.”

The paradigm’s promoters didn’t learn the appropriate lessons in the above page regarding “the sense of embarrassment and regret once experienced with the pneumonia quality metric.”

What do you think are the root causes of the Surviving Sepsis Campaign’s agenda?

  • Did it start with lawyers? Lawsuits can force hospitals into actions for which the primary reason is to avoid “the potential penalties associated with noncompliance.”
  • Is it due to governments? Governments can force hospitals into actions “without any evidence of benefit or knowledge of the logistic consequences or cost” when the hospitals accept government reimbursement.
  • Did it start with other groups of unaccountable people who think they know better than everyone else about how others should act?

https://www.sciencedirect.com/science/article/pii/S0196064418306073 “The 2018 Surviving Sepsis Campaign’s Treatment Bundle: When Guidelines Outpace the Evidence Supporting Their Use” (not freely available)

Epigenetic transgenerational inheritance of ovarian disease

This 2018 Washington rodent study investigated ovarian disease in F3 great-granddaughters caused by their F0 great-grandmothers’ exposures to DDT or vinclozolin while pregnant:

“Two of the most prevalent ovarian diseases affecting women’s fertility and health are Primary Ovarian Insufficiency (POI) and Polycystic Ovarian Syndrome (PCOS). POI is characterized by a marked reduction in the primordial follicle pool of oocytes and the induction of menopause prior to age 40. POI currently affects approximately 1% of female population. While genetic causes can be ascribed to a minority of patients, around 90% of POI cases are considered idiopathic, with no apparent genetic link nor known cause.

PCOS is a multi-faceted disease that affects 6-18% of women. It is characterized by infrequent ovulation or anovulation, high androgen levels in the blood, and the presence of multiple persistent ovarian cysts.

For both PCOS and POI other underlying causes such as epigenetic transgenerational inheritance of disease susceptibility have seldom been considered. Epigenetic transgenerational inheritance is defined as “the germline transmission of epigenetic information and phenotypic change across generations in the absence of any continued direct environmental exposure or genetic manipulation.” Epigenetic factors include:

  • DNA methylation,
  • Histone modifications,
  • Expression of noncoding RNA,
  • RNA methylation, and
  • Alterations in chromatin structure.

The majority of transgenerational studies have examined sperm transmission of epigenetic changes due to limitations in oocyte numbers for efficient analysis.

There was no increase in ovarian disease in direct fetal exposed F1 [grandmothers] or germline exposed F2 [mothers] generation vinclozolin or DDT lineage rats compared to controls.

The transgenerational molecular mechanism is distinct and involves the germline (sperm or egg) having an altered epigenome that following fertilization may modify the embryonic stem cells epigenome and transcriptome. This subsequently impacts the epigenetics and transcriptome of all somatic cell types derived from these stem cells.

Therefore, all somatic cells in the transgenerational [F3] animal have altered epigenomes and transcriptomes and those sensitive to this alteration will be susceptible to develop disease. The F3 generation can have disease while the F1 and F2 generations do not, due to this difference in the molecular mechanisms involved.

The epimutations and gene expression differences observed are present in granulosa cells in the late pubertal female rats at 22-24 days of age, which is long before any visible signs of ovarian disease are detectable. This indicates that the underlying factors that can contribute to adult-onset diseases like PCOS and POI appear to be present early in life.

Ancestral exposure to toxicants is a risk factor that must be considered in the molecular etiology of ovarian disease.”

1. The study highlighted a great opportunity for researchers of any disease that frequently has an “idiopathic” diagnosis. It said a lot about research priorities that “around 90% of POI cases are considered idiopathic, with no apparent genetic link nor known cause.”

It isn’t sufficiently explanatory for physicians to continue using categorization terminology from thousands of years ago. Science has progressed enough with measured evidence to discard the “idiopathic” category and express probabilistic understanding of causes.

2. One of this study’s coauthors made a point worth repeating in The imperative of human transgenerational studies: What’s keeping researchers from making a significant difference in their fields with human epigenetic transgenerational inheritance studies?

3. Parts of the study’s Discussion section weren’t supported by its evidence. The study didn’t demonstrate:

  • That “all somatic cells in the transgenerational animal have altered epigenomes and transcriptomes”; and
  • The particular “molecular mechanisms involved” that exactly explain why “the F3 generation can have disease while the F1 and F2 generations do not.”

https://www.tandfonline.com/doi/abs/10.1080/15592294.2018.1521223 “Environmental Toxicant Induced Epigenetic Transgenerational Inheritance of Ovarian Pathology and Granulosa Cell Epigenome and Transcriptome Alterations: Ancestral Origins of Polycystic Ovarian Syndrome and Primary Ovarian Insuf[f]iency” (not freely available)

The imperative of human transgenerational studies

The coauthor of:

pointed out the opportunity for the researchers of A seasonal epigenetic effect of conception on BMI to have their work make a difference in their field:

“The ability of environmental epigenetics to promote an adaptive phenotype to cold has impacts on evolution. However, the impacts would be far greater if the phenomenon was transgenerational.

Future studies are now needed to determine whether the cold-induced thrifty metabolic phenotype is transmitted to subsequent generations. If exposure not only impacts the health of offspring, but also of all subsequent generations, the impact is significant.”

Every human alive today has observable lasting epigenetic effects caused by environmental factors:

  • During the earliest parts of our lives;
  • From our parents’ exposures and experiences before we’re conceived – many of which are inadequately researched; and
  • Potentially from some of our earlier ancestors’ exposures and experiences.

Aren’t animal studies’ evidence for epigenetic transgenerational inheritance sufficient to compel serious human follow-on research efforts by research sponsors and study designers? The same comments about epigenetic effects caused by temperature potentially inherited by multiple human generations can also be made about other environmental factors, such as:

  • Nutrition,
  • Toxins – the commentator’s usual area of study, and
  • Stress.

I hope that these researchers value their professions enough to make a difference with this or other areas of their expertise. And that sponsors won’t thwart researchers’ desires for difference-making science by putting them into endless funding queues.

https://www.nature.com/articles/s41591-018-0187-3 “Preconception cold–induced epigenetic inheritance” (not freely available)