Reference Ranges for All: Implementing Reference Ranges for Transgender and Nonbinary Patients

Abstract

Objectives  This study aimed to highlight the necessity of developing and implementing appropriate reference ranges for transgender and nonbinary (TGNB) patient populations to minimize misinterpretation of laboratory results and ensure equitable health care.

Case Report  We describe a situation where a TGNB patient's abnormal laboratory values were not flagged due to undefined reference ranges for gender “X” in the Laboratory Information System (LIS). Implementation of additional reference ranges mapped to sex label “X” showed significant improvement in flagging abnormal lab results, utilizing sex-invariant reporting as an interim solution while monitoring developments on TGNB-specific reference ranges.

Conclusion  Informatics professionals should assess their institution's policies for registration and lab reporting on TGNB patients as nonimplementation poses significant patient safety risks. Best practices include using TGNB-specific reference ranges emerging in the literature, reporting both male and female reference ranges for clinical interpretation and sex-invariant reporting.

Background and Significance

Transgender and nonbinary (TGNB) individuals face unique challenges in the health care system, 1 including the potential for inaccurate interpretation of laboratory results due to a lack of appropriate reference ranges. 2 This case report describes a situation in which a TGNB patient's abnormal laboratory values were not flagged in the Electronic Health Record (EHR) due to their gender being labeled as “X,” a value for which reference ranges had not been defined in the Laboratory Information System (LIS).

This case highlights the importance of developing and implementing appropriate reference ranges for TGNB patient populations to minimize misinterpretation of laboratory results and ensure equitable health care. We describe the current literature regarding new reference ranges, 3 practical advice for reporting them under uncertainty, and steps clinical informaticists can take to define risk in their clinical systems.

One of the most significant informatics workflow improvements in laboratory medicine is the automation of laboratory results to the EHR. Reliable notification to clinicians of normal and abnormal laboratory values is critical to medical decision-making. By “flagging” abnormal results in the EHR, clinicians streamline their review process and can identify areas for further inquiry or follow-up, especially when a single patient encounter can result in dozens of results. This form of clinical decision support has become ubiquitous in EHRs. An abnormal result that goes unflagged could pose a significant patient safety risk if it is erroneously assumed to be normal by a provider.

A technical prerequisite for an EHR to flag abnormal lab results is the presence of a “normal” reference range. Reference ranges are typically stored within an LIS. Common LISs in U.S. health care include Beaker (Epic; WI), Soft (SSC Soft Computer; FL), and Sunquest (Clinisys; AZ), the latter of which is used at our institution. TGNB patients are at risk of nonflagged abnormal lab results due to a relative lack of established reference ranges in these specific patient populations. 4

We describe our awareness of the problem through a prototypical case in which the above theoretical harms became a reality. Using the case as a springboard, we then discuss emerging best practices in the literature for identifying and mitigating reference range gender biases in the LIS. The discussion entails the consideration of sex-invariant (“safety range”) reporting as a transition to TGNB-specific reference ranges. Sex-invariant reporting calculates a normal reference range as the intersection between male and female ranges, serving as an interim solution until more specific references can be established. We conclude with a call-to-action for the reader to assess their LIS' ability to flag laboratory values for TGNB patients accurately. 5

Case Report

A 27-year-old nonbinary adult presented to the Emergency Department with abdominal pain. Relevant lab tests were ordered, including liver function tests. Upon completion, the EHR did not flag the patient's results as abnormal. Clinicians noticed these results as abnormal hours after the results were first viewed ( Fig. 1 ).

Fig. 1.

The top panel represents the nonbinary patient's LFT lab results, for which gender was marked as “X” in the EMR. For comparison, the bottom panel is a cisgender male patient's lab results, for which gender was marked in the EMR as “M” (male). Note that the male patient's report, which resulted only minutes after the transgender patient, contains reference ranges and an abnormal results flag. EMR, electronic medical record; LFT, liver function test.

A retrospective analysis of the case revealed that the labeling of the patient's gender in the EHR as “X” by the registration staff was at the patient's request. This was consistent with our hospital's protocols for registering nonbinary patients. With no apparent human error identified, the focus went to the transfer of HL7 messages between the EHR and LIS.

HL7 is an international standard for transferring clinical and administrative data between medical software. 6 An HL7 message incorporates a “Patient Identification segment” that includes identification and health-related information.

Network analysis identified a technical gap in the receiving of input to the LIS. Our LIS utilizes the sex field to determine which sex-specific reference ranges to return. In our LIS default configuration, receiving an HL7 message with a sex other than “M” or “F” returns a silent error. Thus, no reference range is shared with the EHR, and no highlighting of abnormal results is possible. The patient continued to be monitored in an outpatient setting but is otherwise healthy.

A group of laboratory professionals, including laboratory directors, clinical informaticists, and lab technologists, was convened to address the patient safety gap.

In our LIS, we implemented additional reference ranges mapped to the sex label “X.” Reference ranges accompanied a total of 3,905 laboratory test components; 3,090 of these components had the same reference range for both males and females, and 815 components had different ranges for males and females. We utilized sex-invariant reporting as a stop-gap solution while we continued to monitor developments on TGNB-specific reference ranges. This methodology calculates a normal reference range for TGNB patients as the intersection of male and female ranges ( Fig. 2 ).

Fig. 2.

An example, using AST, of sex-invariant reporting. This process calculates the “safest range” for an unspecified sex “X” using previously established sex-specific reference ranges. The new reference range is the intersection of male and female ranges, creating a narrower “normal” range from the highest lower bound and lowest upper bound. Intuitively, this method flags values as normal if it would be normal in both males and females and is thus invariant to sex. AST, aspartate transferase.

Because sex-invariant reference ranges are constructed from already available reference ranges, they can be computed quickly. However, this method can produce an overly narrow range for labs with minimally overlapping reference ranges between sexes. An unduly narrow range will produce false positives at a higher rate, potentially alarming clinicians and patients. A manual review of the reference ranges at our institution found this was largely the case for hematology tests such as hemoglobin. To mitigate this in our implementation, we used a “widest range” for hematology values to reduce false positives, and a sex-invariant range for all other labs.

Lastly, the estimated glomerular filtration rate (eGFR) and hormone tests were given special consideration. Because eGFR calculations are sex-specific and our LIS can only return one result, we are considering calculating the eGFR for TGNB patients using female parameters for additional sensitivity. Using “female” parameters in the calculation yields a lower eGFR, thus more sensitively indicating potentially compromised kidney function. 7

Hormone reference ranges for TGNB populations are an area of active research. 8 Current studies have not yielded an algorithmic method for determining whether a given patient should use cisgender male or female reference ranges. Because the sex-specific values of hormone reference ranges often do not overlap, they were not amenable to a sex-invariant calculation. After discussion with our endocrinology service, we decided to report both female and male reference ranges for hormone tests ordered on TGNB patients.

Discussion

Depending on the LIS and electronic medical record (EMR) used, a patient may have varying entries in fields such as “gender,” “legal sex,” “administrative sex (sex used for billing purposes),” and “sex assigned at birth.” These fields are often user-defined at the institution level. Our institution's specific table utilized “M,” “F,” “X,” and “unknown” to convey administrative sex within HL7 messages. Because our LIS did not have reference ranges defined for the “X” or “unknown” label for sex, it could not return an appropriate reference range or quality flags (i.e., abnormal or critical values).

TGNB patients are at a unique risk of unflagged abnormal laboratory values due to a lack of established reference ranges, nonstandardized nomenclature in health IT systems, and organizational structures that have historically neglected TGNB gender identity. 5

Sex-invariant reporting may be controversial 9 if viewed as the definitive answer to the necessity of TGNB reference ranges. Sex-invariant reporting is not an alternative to continued investigation of TGNB reference ranges. When reviewing this method as an intermediate step to improve patient safety, our institution decided that the presence of reference ranges was safer than the absence of reference ranges for this population. 5 A more durable solution would be establishing evidence-based reference ranges tailored to the TGNB community. Setting these ranges would involve extensive research, incorporating a broad spectrum of individuals from this community. However, given the diversity within the TGNB population and the challenges associated with conducting large-scale studies, these reference ranges may remain elusive.

Conclusion

We present a near-miss in which a TGNB patient's abnormal lab results were initially missed, due to a silent error in the LIS–EHR interface for patients with a reported gender other than male or female. Informatics professionals should investigate their institution's policies for registration and lab reporting on TGNB patients as nonimplementation of these ranges poses a significant patient safety risk. 10 Introspection should begin with workflow for registering TGNB patients to ensure consistent and logical use of labels, such as “X” for patients that identify as neither male nor female. Interoperable communication (such as HL7) messages should be analyzed to ensure that sex labels beyond “M” and “F” are recognized by the LIS. Creating TGNB test patients in a sandbox environment can confirm a working data pipeline.

Current best practices for defining reference ranges for TGNB patients include using TGNB-specific reference ranges emerging in the literature, 3 reporting both male and female reference ranges for clinical interpretation, and sex-invariant reporting (defined as the intersection of male and female reference ranges). 10 11

Clinical Relevance Statement

This study underscores the critical need for inclusive health informatics practices that recognize the diversity of patient identities. By implementing sex-invariant reference ranges, health care providers can remove obstacles toward the consistent flagging of lab values for TGNB patients.

Multiple-Choice Questions

1. What is a primary challenge faced by TGNB individuals within the health care system?

   1. Overrepresentation in clinical studies

   2. Lack of appropriate reference ranges

   3. Excessive clinical decision support alerts

   4. Overly broad diagnostic categories

   Correct Answer : The correct answer is option b. TGNB individuals often face inaccurate interpretations of laboratory results due to the lack of appropriate reference ranges tailored to their specific health needs.

2. Which method was utilized as an interim solution while monitoring developments on TGNB-specific reference ranges?

   1. Gender-exclusive reporting

   2. Age-adjusted referencing

   3. Sex-invariant reporting

   4. Ethnicity-based adjustments

   Correct Answer : The correct answer is option c. Sex-invariant reporting calculates a normal reference range as the intersection between male and female ranges, serving as an interim solution until more specific references can be established.

3. What action is recommended for informatics professionals regarding LIS systems?

   1. Disabling automatic flagging features for TGNB patients

   2. Assessing policies on TGNB patient registration

   3. Remove reporting of reference ranges for TGNB patients

   4. Increasing reliance on manual data entry

   Correct Answer : The correct answer is option b. Explanation: Informatics professionals should assess their institution's policies related to registering TGNB patients ensuring consistently used labels like “X” are recognized by LIS systems.