Table 1.
The fundamental issues and considerations in studies of early detection biomarker discovery and validation: discussion from the meeting*
| Issue | Consideration | Discussions |
|---|---|---|
| Study design | ||
| Fundamental comparison |
Internal validity: If the fundamental comparison is biased—with a systematic difference between the compared groups—then results will not be reproducible or valid. | The process of collecting subjects, specimens, and data should be reported using accepted reporting guidelines such as STARD (15,16). Consideration should be given to whether any aspect of the comparison would be considered a serious or fatal bias. The PRoBE approach (prospective specimen and data collection and blinded retrospective evaluation) (20) helps provide features of design and conduct that avoid bias and ensure internal validity. |
| Subjects | External validity: Methods should assure that subjects can be determined to be asymptomatic when specimens are collected. | Periodic collection of serial samples at prespecified intervals within a cohort followed over time helps assure that symptoms are not the reason that a specimen was collected. Use of prediagnostic samples also allows earlier detection than clinical detection, helping to differentiate useful biomarkers from acute phase proteins. |
| Specimens/data | Specimens should be collected serially over time. | Frequent serial collection helps assure that a specimen will be available near and before the time of cancer diagnosis, and prior to biopsy or other change that occurs after diagnosis is established. Specimens collected prior to outcome will be handled blinded to outcome status. The PRoBE approach, which involves collecting (and storing) before the outcome occurs, helps avoid bias in handling, processing, and storage between case patients and control patients. |
| Outcome | All subjects should be followed with similar intensity to ascertain the outcome. | Unequal follow-up may lead to preferential ascertainment in persons with symptoms or with a positive test result. In a formal prospective research cohort, uniform methods to assess outcome are often utilized. In clinical cohorts, such as within HMO settings, special procedures may need to be created to ascertain outcomes similarly in all subjects. |
| Logistics | ||
| Sample collection | Special collection procedures may be needed for biological molecules to maintain integrity (eg, protein, mRNA); special handling procedures (collection, centrifugation, freezing, etc.) may be needed. | Appropriate standard operating procedures for sample collection and handling may be needed. |
| Sample storage | Sample storage may be costly for biospecimens like serum, plasma, etc. | Centralized storage and economy of scale may help to alleviate costs. Support should be considered for continued storage of specimens after a study has ended. |
| Specimen sharing | Appropriate specimens may have already been collected in NCI-sponsored trials and studies. | An inventory of NCI-funded studies that collected prediagnostic biospecimens may identify resources that already exist and can be used for earlier detection biomarker studies. Such an inventory would need to include not only details of specimens but also of the purpose, design, and conduct of the cohort studies that led to their collection. An ongoing dialogue among groups that have applied or developed appropriate methods to create unbiased sample and data collection is needed. |
| Process sharing | Material transfer agreements and data use agreements may be hard to facilitate. | Existing infrastructures created by the NIH and other groups (eg, NIH TAD system) to ease burden on researchers. |
* HMO = health maintenance organization; NCI = National Cancer Institute; NIH = National Institutes of Health; NIH TAD = NIH’s Transfer Agreement Dashboard; PRoBE = Pivotal Evaluation of the Accuracy of a Biomarker Used for Classification or Prediction; STARD = Standards for the Reporting of Diagnostic accuracy studies.