Flags are used to indicate potential customers or orders of concern that require attention.
Effective biosecurity sequence screening programs screen both customers and orders. Customers are screened to ensure the veracity of the customer information and their need for the materials ordered. Sequences are screened against control lists and sequence reference databases to ensure that sequences of concern are identified and reviewed before the order is filled.
Customer Screening Flags
Guidances such as the U.S. HHS 2010 Screening Framework Guidance and the IGSC Harmonized Screening Protocol include provisions for the evaluation of the customer in a transaction involving potential sequences of concern. These provisions call for customer veracity to be screened at several levels. The process includes the following questions:
Is this customer known to you?
Is there anything unusual about this order from this customer?
If not known to you, does this customer exist?
Is customer information accurate?
Is the customer acting as a middleman, or is the customer the end-user?
Does the customer have a legitimate need for this material?
Has the customer requested alternative shipping and/or payment arrangements?
Does this customer meet the norm for the customer type and the materials ordered?
When the answer to any of the above questions does not satisfy the screening requirements, the customer screening portion of the biosecurity screening program will flag that item. The flag indicates that something is outside the norm and requires additional investigation. This investigation can be as simple as verifying an address or as serious as notifying law enforcement of a potential bad actor. As the synthetic biology industry grows and more customers come into the arena, the use of standardized customer screening protocols that result in flags when not met is an essential first step to effective biosecurity.
Sequence Screening Flags
Screening for the actual sequence orders requires consideration of the controls on pathogens at the domestic and international level, along with the controls for sequences.
Control lists are compiled and used on an international basis. They name organisms with the potential to pose a severe threat to public, animal, or plant health. These control lists are updated on a regular basis and include restrictions on the export of specific organisms. A flag arising from a control list indicates that the requested sequence is associated with a controlled organism either not permitted for sale without the right authorizations in the U.S., or at all, or is not permitted to be exported from the U.S. Follow-up for this type of flag is essential.
Controls on sequences should be part of all biosecurity screening programs. A flagged sequence indicates that it matches or has high homology to a known sequence of concern. The sequence reference databases include annotated data about the sequences that assist in the assessment of the threat. It can be very time consuming reviewing these matches, but fortunately, tools like Battelle’s ThreatSEQ DNA Screening Service provide information related to virulence, antibiotic resistance, immune evasion factors, human bioregulators, protein toxins, and other threat factors, and assigns a threat score to a sequence of concern. This information is provided in a concise report that can be used to determine the necessity of follow-up.
False Positive and Negatives
Screening systems can sometimes flag sequences as concerning when they are not - this is called a false positive. A sequence that is not flagged when it should be is known as a false negative. In either case, a thorough investigation is required to ascertain the reason behind the incorrect flags. Refinements to the screening parameters and sometimes the reference databases themselves are required.
In short, flags alert those monitoring the customers and sequences that something is outside the safe parameters. In the case of customer screening, it will likely be about the veracity of the information and the fit of the order to the customer’s stated business purpose. For sequences, it will likely be because screening has identified a sequence on a control list, and therefore ensuring the customer is authorized to work with the sequence is required.