Bioethics for lab medicine

 Ethics for Laboratory Medicine

Key issues:

Table 1.Ethical Issues of particular importance in Laboratory medicine.

Informed consent 

Use of leftover specimens 

Biobanking 

Genetic testing 

Equity and access to laboratory testing 

Incidental findings and medically actionable results 

DTC testing 

Transfusion medicine and religious or ethical restrictions 

Disclosing medical error 

Emerging infectious diseases 

Test utilization 

The unique role of laboratorians, who care for patients but interact mainly with their samples rather than the person, creates distinct ethical dilemmas. In addition, laboratories function as critical parts of complex health systems, and the interaction of the laboratory with the greater healthcare system creates additional points of ethical friction (45). Clinical laboratory professionals are ethically bound to use our voices to advocate for excellence in patient care in the realms of respect for persons, beneficence, and justice, even in the face of technological, administrative, and, perhaps, clinical pressures to do otherwise.

Ethics represents moral principles based on cultural norms and values. Sometimes these moral values have been turned into federal or state laws or into local rules and regulations. However, laws and rules may be absent or difficult to apply to a given situation. When faced with ethical decisions, laboratorians should seek the input from other clinicians and laboratory colleagues. In addition, most hospitals have ethics boards comprising multidisciplinary teams of clinicians, lay people, and clergy to help guide decision-making.

 

Regulatory uncertainty in "home-brew" lab testing

Laboratory-Developed Tests: A Legislative and Regulatory Review

In vitro diagnostics regulation requires continuous adaptation to technologic innovation. Unfortunately, there is a lack of understanding that such a crucial task should be performed efficiently. Europe has waited 23 years for a new regulation!. Anyway, US is under the same trend. Laboratory developed tests were initially regulated 25 years ago and there are still pending issues in the new draft legislation. If you want to know the details, an article in Clinical Chemistry explains the whole issue.

A quarter of a century after the FDA first asserted regulatory authority over LDTs in a draft guidance document, rules and/or guidance regarding LDT oversight have not been implemented. As such, legal questions regarding MDA authority over LDTs and the FDA draft guidance approach have neither been escalated to nor resolved by the judiciary. In addition, many questions central to this debate have not been answered. Are clinical laboratories manufacturers? Should laboratory devices and procedures be regulated similarly? Are there always clear limits between laboratory operations and the practice of laboratory medicine? Any future LDTregulatory or legislative efforts will need to balance and address these concerns if they are to be successful. It is unlikely that interpretation of current statutes and regulations can fully resolve these issues.

 Josep Moscardó, Barcelona landscape

The anxiety of inaccuracy

Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing

What happens if "one quarter of the clinical genetic results from commercially available multiplex cancer panels and reported at the PROMPT registry had conflicting interpretations" and if "36% of conflicting genetic tests results appeared to be clinically relevant, because they were either reported as pathogenic/likely pathogenic"? Does anybody care about it?.
I would suggest today you have a look at this article and your level of anxiety will increase suddenly.

Clinical data and genetic testing results were gathered from1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall,participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis.

Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management.

Therefore, 

Clinical interpretation of genetic testing for increased cancer susceptibility as assessed by multiplex panels hinges on accurate curation and interpretation of variants. Discrepant interpretation of some genetic variants appears to be common.

Take care. The regulator remains on vacation, a never ending vacation.

PS. On genetic testing 

 Vivian Mayer

DNA methylation assays as epigenetic biomarkers

Quantitative comparison of DNA methylation assays for biomarker development and clinical applications

A new milestone has been achieved in Medicine. Tracking epigenetic alterations is crucial to understand a disease. However, epigenetic biomarkers are needed to assess such changes. Its precision (sensitivity-specifity) is  paramount for its clinical application. Now a group of international researchers has certified its performance (partially). Have a look at this Nature article:

Genome-wide mapping and analysis of DNA methylation has become feasible for patient cohorts with thousands of samples, and epigenome-wide association studies have been conducted for numerous biomedically relevant phenotypes. To translate relevant epigenome associations into clinically useful biomarkers, it is necessary to select a manageable set of highly informative genomic regions, to target these loci with DNA methylation assays that are sufficiently fast, cheap, robust and widely available to be useful for routine clinical diagnostics, and to confirm their predictive value in large validation cohorts.

Among its conclusions I would like to highlight three of them:

(i) Absolute DNA methylation assays are the method of choice when validating DNA methylation differences in large cohorts, and they are also an excellent technology for developing epigenetic biomarkers.

(ii) Relative DNA methylation assays are not a good replacement for absolute assays. However, experiences of scientists in the contributing laboratories suggest that carefully selected, designed and validated relative assays can cost-effectively detect minimal  races of methylated DNA against an excess of unmethylated DNA.

(iii) Global DNA methylation assays suffer from noisy data and divergent results between technologies. Locus-specific assays (possibly combined with prediction) provide a more robust alternative

That's it. Very soon will see the epigenetic biomarkers in routine clinical use. And afterwards,  epigenetic drugs and treatments. Then, we'll confirm that the promise of precision medicine is a reality. The implications for medicine as a scientific discipline and clinical decision making are huge, and specifically, healthcare organizations will need to adapt to new knowledge and technologies.

PS. Neuroepigenetics: DNA methylation and memory

Organising genetic testing

Finally the government has decided to organise genetic counseling and testing. A recent instruction determines who does what. As you may remember I've said several times that government was on permanent holiday on this issue.
In this new instruction, at least two issues are forgotten: the tests that are covered, and the proliferation of sequencing instruments outside the lab. These are not minor issues.
Somebody should decide asap wether a test it is worth to be prescribed. Right now, there are no explicit constraints under the current instruction. And DNA sequencing instruments may be found in many departments under the consideration of research. If there is no clear split between research and care, I can imagine a close future with many messy labs within any hospital. Concentration of knowledge and specialisation provides wider guarantees for quality. Unless there is any mentorship program by clinical laboratories, things will go down the wrong path. Today I'm more worried than yesterday, unless these two issues are fixed.

Keep on improving

On the improvement of blood sample collection at clinical laboratories

Efficiency in healthcare management comes as the result of many decisions and actions. Knowledge can improve such decisions. This weekend I was reading this article on clinical labs and how to collect samples with less routes. With operations research techniques, it is possible. Afterwards there is a need to implement them. The results of the article:

The two laboratories in this study previously planned routes manually for 43 and 74  collection points, respectively. These routes were covered by an external carrier company. With the implementation of this algorithm, the number of routes could be reduced from ten  to seven in one laboratory and from twelve to nine in the other, which represents  significant annual savings in transportation costs

The potential for operations research in healthcare is huge. The incentives to apply it, low (unfortunately).

When asking your physician is not enough

23andMe and the FDA

Some weeks ago I explained the FDA "closure" of DTC genetic testing business. NEJM analyses with detail the rationale behind such policy:

The goal of the FDA and 23andMe (as well as all clinical geneticists, testing laboratories, and the entire genetics industry) should be to ensure that genomic information is both accurate and clinically useful. Clinicians will be central to helping consumer–patients use genomic information to make health decisions. Any regulatory regime must recognize this reality by doing more than simply adding the tagline on most consumer ads for prescription drugs: “Ask your physician.” That is insufficient guidance unless your physician has ready access to a clinical geneticist or genetic counselor.

European regulation is 15 years old and the new directive is still being discussed. It will not be applied for at least 3 years. Meanwhile, do you know who is protecting us from inaccurate and clinically useless information?