Incidental genetic findings in randomized clinical trials: recommendations from the Genomics and Randomized Trials Network (GARNET)

Recommendations and guidance on how to handle the return of genetic results to patients have offered limited insight into how to approach incidental genetic findings in the context of clinical trials. This paper provides the Genomics and Randomized Trials Network (GARNET) recommendations on incidental genetic findings in the context of clinical trials, and discusses the ethical and practical issues considered in formulating our recommendations. There are arguments in support of as well as against returning incidental genetic findings in clinical trials. For instance, reporting incidental findings in clinical trials may improve the investigator-participant relationship and the satisfaction of participation, but it may also blur the line between clinical care and research. The issues of whether and how to return incidental genetic findings, including the costs of doing so, should be considered when developing clinical trial protocols. Once decided, plans related to sharing individual results from the aim(s) of the trial, as well as incidental findings, should be discussed explicitly in the consent form. Institutional Review Boards (IRBs) and other study-specific governing bodies should be part of the decision as to if, when, and how to return incidental findings, including when plans in this regard are being reconsidered

Reporting genetic results in research studies: Summary and recommendations of an NHLBI working group

Cilj rada je prikazati kontroling kao važnu sastavnicu uspješnosti na primjeru malih i srednjih poduzeća u Hrvatskoj. Prikazati će se pojmovno određenje kontrolinga, sistematizacija koncepcija kontrolinga i odnos kontrolinga i drugih funkcionalnih područja s kojima je kontroling povezan. Analizirati će se metode i tehnike analize poslovanja u konkretnom poduzeću što će biti potkrijepljeno istraživanjem na temelju dostupnih primarnih i sekundarnih izvora informacija. U empirijskom dijelu rada analizirati će se zastupljenost kontrolinga u malim poduzećima u Hrvatskoj i uspješnost provođenja kontrolinga

Confirmation of the Reported Association of Clonal Chromosomal Mosaicism with an Increased Risk of Incident Hematologic Cancer

<div><p>Chromosomal abnormalities provide clinical utility in the diagnosis and treatment of hematologic malignancies, and may be predictive of malignant transformation in individuals without apparent clinical presentation of a hematologic cancer. In an effort to confirm previous reports of an association between clonal mosaicism and incident hematologic cancer, we applied the anomDetectBAF algorithm to call chromosomal anomalies in genotype data from previously conducted Genome Wide Association Studies (GWAS). The genotypes were initially collected from DNA derived from peripheral blood of 12,176 participants in the Group Health electronic Medical Records and Genomics study (eMERGE) and the Women’s Health Initiative (WHI). We detected clonal mosaicism in 169 individuals (1.4%) and large clonal mosaic events (>2 mb) in 117 (1.0%) individuals. Though only 9.5% of clonal mosaic carriers had an incident diagnosis of hematologic cancer (multiple myeloma, myelodysplastic syndrome, lymphoma, or leukemia), the carriers had a 5.5-fold increased risk (95% CI: 3.3–9.3; p-value = 7.5×10⁻¹¹) of developing these cancers subsequently. Carriers of large mosaic anomalies showed particularly pronounced risk of subsequent leukemia (HR = 19.2, 95% CI: 8.9–41.6; p-value = 7.3×10⁻¹⁴). Thus we independently confirm the association between detectable clonal mosaicism and hematologic cancer found previously in two recent publications.</p> </div

Characteristics of mosaic anomalies.

<p>A) BAF and LRR metrics for mosaic anomalies by estimated copy change from disomic state (red = loss, dark blue = gain, orange = copy neutral loss of heterozygosity. B) BAF and LRR metrics for mosaic anomalies by location (dark blue = interstitial, turquoise = p terminal, pink = q terminal or red = whole chromosome). C) BAF and LRR metrics for mosaic anomalies by type of chromosome (green circle = acrocentric, purple cross = metacentric). D) BAF and LRR metrics for mosaic (red) and non-mosaic (black) anomalies.</p

Comparison characteristics of hematologic cancer cases and individuals without a diagnosed hematologic cancer during study follow-up.

<p>Comparison characteristics of hematologic cancer cases and individuals without a diagnosed hematologic cancer during study follow-up.</p

Counts of detected mosaic anomalies by chromosomal location and event type.

<p>Counts of detected mosaic anomalies by chromosomal location and event type.</p

Summary of characteristics of studies included in the analysis.

1<p>Number of individuals included and analyzed in study;</p>2<p>Predominant ancestral group;</p>3<p>Age at baseline and/or sample collection;</p>4<p>Only phase 1 data included;</p>5<p>Only phase 2 data included.</p

Mosaic anomalies plotted across chromosome in megabases (mb) by estimated copy change from disomic state (red = loss, dark blue = gain, orange = copy neutral loss of heterozygosity).

<p>The red box around the ideogram represents the region of interest for the plot located below. Chromosome 21 is omitted due to the absence of detected mosaic anomalies on the chromosome. (Note: plots are not drawn to scale).</p

Kaplan Meier plots of the proportion of individuals remaining without diagnosed A) Hematologic cancer stratified by presence (blue) or absence (red) of a mosaic anomaly or B) Leukemia stratified by presence (blue) or absence (red) of a large mosaic anomaly (>2 mb).

<p>Kaplan Meier plots of the proportion of individuals remaining without diagnosed A) Hematologic cancer stratified by presence (blue) or absence (red) of a mosaic anomaly or B) Leukemia stratified by presence (blue) or absence (red) of a large mosaic anomaly (>2 mb).</p