Decision Analysis Model
A decision tree was constructed and probabilities and costs estimated for each of the decision nodes (see Figs. 1–5). Several of the estimates were derived from primary data collection. The remainder of the estimates were derived from published data and unpublished Massachusetts health data. All costs were adjusted to 2002 U.S. dollars and future costs discounted at a rate of 3%. 28
The model incorporates programmatic costs of screening and treatment and medical cost savings from sequelae prevented in infected males and female partners of index males. The time horizon extends to 10 years to incorporate all expected sequelae of untreated chlamydial infection in female partners. Medical outcomes include cases of epididymitis, cases of PID, and cases of chronic pelvic pain, ectopic pregnancy, and infertility. We report on the total cases of PID and epididymitis prevented, the total costs saved, and the incremental costs of each screening strategy compared with no screening. The analyses are conducted from the healthcare system perspective.
We conducted a chlamydia prevalence study among a consecutive sample of 678 adolescent males, aged 14 to 18 years old, entering 2 Central Massachusetts detention facilities (Worcester and Westboro, MA) between February 15, 2001, and February 27, 2003. Detainees were eligible to participate if they were at least 14 years old, had not voided in the previous 1 hour, and had not used any antibiotics in the previous 3 weeks. A research assistant described the study protocol and emphasized the strictly voluntary nature of the study to potential participants. Written informed consent was obtained from all participants. Because this was a minimal risk study and involved STD diagnosis, the requirement for parental permission for minors was waived. Study protocol and consent procedures were approved by the University of Massachusetts Medical School Committee for the Protection of Human Subjects in Research.
A research assistant administered a brief interview to participants that included demographics, history of sexual intercourse, and symptoms experienced in the preceding 5 days. After completing the interview, participants were instructed on proper urine collection technique and asked to obtain the first 10 to 15 cc of voided urine in a plastic centrifuge tube. Urine samples were first tested for LE and then stored at 2° to 8°C until transport. LE test strips (Chemstrip 9; Roche Diagnostics; Indianapolis, IN) were read at between 60 and 120 seconds, per manufacturer’s instructions, and recorded as negative, trace, 1+, or 2+. Urine samples were shipped on ice packs by overnight delivery to The Johns Hopkins University Chlamydia Research Laboratory in Baltimore, Maryland, where they were tested for chlamydia using either the LCx (Abbott Laboratories, Abbott Park, IL) or BDProbeTec (Becton Dickinson, Sparks, MD) nucleic acid amplification assay, as per manufacturers’ instructions.
The physician assistant at the detention program was contacted with all positive test results. If patients were still present in the program, they were treated promptly with one oral dose of 1 g azithromycin. If a patient had left the program before receipt of a positive test result, the research assistant attempted to make contact with him by telephone. Depending on patient preference, a prescription for 1 g azithromycin was phoned into a local pharmacy or the patient was given the address and phone number of the local STD clinic. In either case, the research assistant phoned back a few days later to confirm that he had received treatment. If the research assistant could not locate the patient by phone or was unable to confirm that treatment had occurred, the Department of Public Health was contacted and a Disease Intervention Specialist attempted to make contact with the patient to assist with treatment. At the time of notification, patients testing positive for chlamydia were asked how many sexual partners they had had in the previous 2 months (0, 1, 2, or >2). They were also encouraged to refer their sexual partners for treatment.
The probabilities of events in the decision tree were estimated from primary data collection, published studies, and unpublished data from state and local sources (Table 1).
A modified metaanalysis was performed using a Medline search for all published articles evaluating the sensitivity and specificity of urine LCx and BDProbeTec for detection of chlamydia in males. 3–7,29–42 See the Appendix for details of the modified metaanalysis. Studies assessing the probability that an infected male will transmit a chlamydia infection to his female partner have reported rates of 58% to 68%. We used the median value of 65% as our estimate. 43–45 The proportion of female partners of infected male patients who receive treatment varies widely among published reports and depends on the method of contact tracing chosen. 46–48 We used the midrange value of 55% as our estimate of the effectiveness of partner notification. Few data are available regarding the proportion of untreated males who develop chlamydial epididymitis. Based on published reports, we have estimated that 5.2% of untreated males will develop epididymitis and 8.7% are hospitalized for treatment. 49,50
Most studies evaluating the probability that an untreated infected female will develop PID have reported a range of 30% to 40%. 14,51–53 We chose the midpoint of 35% as our estimate. Although definitive data on the proportion of all PID that is “silent” or asymptomatic is not available, it has been estimated that 60% of PID is subclinical and 40% is overt. 14,54 Hospitalization for PID treatment ranges from 5% to 25% in the literature. 2,55–59 We chose the median value of 12.1% for our estimate. An estimated 18% of women with a history of PID will develop chronic pelvic pain 59 and an estimated 6% will have an ectopic pregnancy. 59–62 Risk of infertility rises dramatically with additional episodes of PID. For the purposes of this study, risk of infertility after one episode of PID was used and is estimated at 9%. 59,60,62 An estimated 22.4% of infertile women will seek services to assist in becoming pregnant. 63
Actual costs were obtained from Massachusetts state data, Department of Youth Services salary data, and costs of supplies used to collect and test urine for LE. When actual costs were not available, estimates were derived from the literature. Cost-to-charge ratios were used to calculate costs when only charge data were available. Medicaid reimbursement rates were assumed to be approximately equivalent to cost. Cost estimates are summarized in Table 2.
A time-in-motion study was performed by the principal investigator to estimate the labor costs associated with collecting urine specimens and performing LE testing. The principal investigator observed and timed the research assistant’s collection and packaging of urine samples as well as performance of urine LE testing for 5 participants. The average amount of time to collect urine and to perform LE testing on the urine was determined and was multiplied by the midrange salary of a nurse practitioner or physician assistant working for the Massachusetts Department of Youth Services (DYS).
Other costs associated with sample collection include that of the urine container, the LE testing strip, and daily transport of the urine to the Massachusetts Department of Public Health (DPH) State Laboratory where it is assumed that future urine samples will be processed. The Massachusetts Medicaid reimbursement rate was not used for the chlamydia NAAT processing cost estimate because chlamydia NAATs are processed onsite at the Massachusetts Department of Public Health State Laboratory such that the cost incurred by the state laboratory to do the processing is more relevant. Therefore, we derived the estimated NAAT cost ($10) from the literature. 12,13,16,64
For participants who tested positive for chlamydia and were still in the custody of DYS at the time that their result was received, it was estimated that a clinician would spend 15 minutes treating and counseling them. This estimate was multiplied by the midrange salary of a nurse practitioner or physician assistant working for the Massachusetts DYS. Treatment of participants who have left DYS before notification of positive test results was estimated from the Medicaid reimbursement rate at UMass Memorial for a level 3 office visit (approximately 15 minutes). The cost of a physician visit for partners of infected participants was estimated from the Medicaid reimbursement rate at UMass Memorial for a level 4 office visit (approximately 25 minutes). The cost of one oral dose of 1 g azithromycin was estimated from the Massachusetts Medicaid reimbursement rate. For participants requiring the assistance of the Department of Public Health’s Disease Intervention Specialist (DIS), cost of this service was estimated from the midrange salary of the DIS multiplied by an estimated average of 2 hours spent per client treated.
The cost of inpatient treatment for epididymitis and PID were derived from the literature as well as from the Northeast regional data of the Healthcare Cost and Utilization Project (HCUP) 2000. 2,49 Outpatient treatment costs of epididymitis and PID were estimated from the Medicaid reimbursement rate at UMass Memorial for a level 5 office visit (approximately 40 minutes) for initial diagnosis and treatment and for a level 4 follow-up office visit. Medication costs for an intramuscular injection of ceftriaxone and 10 to 14 days of oral doxycycline were derived from the literature. 65,66 The injection administration cost was conservatively estimated at $5. It has been estimated that costs incurred for treatment of PID occur in the first year after acquiring a chlamydia infection. 67
The costs for treatment of infertility, ectopic pregnancy, and chronic pelvic pain were derived from the literature and the Northeast regional data of HCUP 2000. 2,10,12,16,55,59,68–70 Costs incurred for infertility have been estimated to occur in the 10th year after PID, those for ectopic pregnancy occur in the fifth year after PID, and those for chronic pelvic pain in the second year after PID. 59 A 3% discount rate was applied to these costs.
DATA PRO, a computer-based decision tree program produced by TreeAge Software Inc. (Williamstown, MA), was used to conduct the cost-effectiveness analyses using the estimated probabilities and costs detailed previously. Medical outcomes used in the analyses include epididymitis, PID, chronic pelvic pain, ectopic pregnancy, and infertility. The number of cases of PID prevented was used as the primary outcome associated with each screening strategy. Total and incremental costs, total and incremental effectiveness, and cost-effectiveness and incremental cost-effectiveness ratios associated with each screening strategy are reported.
A threshold analysis (parameter value at which recommendations would change) was conducted to determine the prevalence of chlamydia infection above which cost savings are generated by each of the 2 screening strategies.
Because the cost-effectiveness analyses rely on many probability and cost assumptions, univariate and bivariate sensitivity analyses were conducted to determine what effect a variation in one or more of the probabilities or costs would have on the outcome. Univariate sensitivity analyses were performed for all variables, and bivariate analyses were performed when appropriate to further evaluate the strength of the model.
Characteristics of Study Participants
Eight hundred thirty-five youth were invited to participate. Based on the detention facility census reports, we estimate that we approached approximately half of all detainees. Eighty-four (12.4%) of the 678 who agreed to participate denied sexual experience. Because none of these participants tested positive for chlamydia infection, we included only those who were sexually experienced in the analysis (n = 594). The mean age of this 14- to 18-year-old sample was 15.6 years (standard deviation [SD], 0.9). Racial and ethnic composition were 40% white, 38% Hispanic, 8% black, 9% multiracial, 4% Asian, and 1.0% other race.
Chlamydia prevalence in the sampled population was 4.8% (95% confidence interval, 3.2–6.8%). The point estimate of the true prevalence (4.8%) was calculated by dividing the observed proportion of infected males (0.044), as defined by a positive NAAT, by the sensitivity of the NAAT (0.913). The average number of female sexual partners/infected male in the preceding 2 months was 1.6, and 84.6% of infected males were asymptomatic. None of the infected participants were lost to follow up and 77% were treated onsite.
Urine samples from 16 (61.5%) male youth infected with chlamydia were trace-positive by LE, yet only 11 (42%) were 1+ positive by LE. As expected, the specificity of LE was higher for a 1+ cutoff (95.8%) than for a trace cutoff (80.6%). However, sensitivity was deemed more important; hence, trace was used as the LE-positive cutoff in the analysis.
One hundred fifty-seven (18.8%) eligible males declined participation. Mean age of those declining participation was 15.5 years (SD, 0.9); racial and ethnic composition was 55.1% white, 17.3% Hispanic, 5.8% black, 12.8% multiracial, 6.4% Asian, and 2.6% other race. The most common reasons given were not interested (58%), recently tested (11%), and does not think he could have an infection (10%). Mean age of participants did not differ significantly from those who declined, but racial and ethnic composition did differ significantly (chi-squared = 26.28, df = 4, P <0.001).
For the hypothetical cohort of 4000 males detained per year, selective NAAT screening of those with a trace positive LE prevented 62 cases of PID, 11 cases of chronic pelvic pain, 4 cases of ectopic pregnancy, and 6 cases of infertility in past and future female partners, as well as 6 cases of epididymitis in index males, saving $59,000 compared with no screening (Table 3). Universal NAAT screening prevented an additional 37 cases of PID, 7 cases of chronic pelvic pain, 2 cases of ectopic pregnancy, 3 cases of infertility, and 3 cases of epididymitis, saving an additional $24,000 compared with selective screening. Threshold analyses demonstrated that universal screening remained the most cost saving for chlamydia prevalence as low as 2.8% or higher, and selective screening remained cost saving for prevalence as low as 1.7%.
Cost of the Nucleic Acid Amplification Test.
The model was sensitive to cost of the NAAT, and selective screening of LE-positive males became more cost saving than universal screening when the NAAT cost exceeded $18. However, even at a NAAT cost of $20, the incremental cost-effectiveness ratio of universal screening was only $195 per additional case of PID prevented.
Female Partners of Index Males.
The model was very sensitive to number of female partners. We made the assumption that adolescent males will have approximately the same number of new partners over the ensuing 2 months as they report over the previous 2 months. Two-way sensitivity analysis demonstrated that universal screening remains more cost saving than selective screening if past and future partners are at least 0.9 (see Fig. 4). Holding past partners at 1.6, 1-way sensitivity analysis demonstrated that universal screening remains more cost saving than selective screening if future new partners are at least 0.6 (see Fig. 5).
Two other considerations are that not all future partners will enter the relationship chlamydia-free, and some infected past partners could receive treatment without partner notification. If we assume that 10% of potential future partners are already infected, then only 90% of future partners will be protected from contracting an infection as a result of treatment of the index male. This translates to 1.4 future partners rather than 1.6. Similarly, if 20% of infected past partners received treatment without partner notification, then only 80% of notified and infected past partners benefit from infection detection of the index male. This translates to 1.3 past partners rather than 1.6. For both of these scenarios, the number of past and future partners remains above the threshold of 0.9 in which universal screening remained the most cost saving.
Rate of Pelvic Inflammatory Disease Development
Universal screening remained the most cost-saving strategy for PID development rates of 20% and higher.
Leukocyte Esterase Sensitivity and Specificity.
Two-way sensitivity analysis demonstrated that selective screening became the most cost-saving strategy for LE sensitivity and specificity above 78% and 83%, respectively.
Pelvic Inflammatory Disease Sequelae Cost.
Wide ranges of PID sequelae costs were found in the literature. 2,12,16,55,59,68–70 If the lowest cost estimates for all 3 sequelae are used simultaneously, the selective screening strategy is the most cost-effective. However, if the highest cost estimates for all 3 sequelae are used simultaneously, universal screening saves $69,000 as compared with selective screening. Our cost and probability estimates for development, treatment, and sequelae of PID are equivalent to an average lifetime cost of $1631, which falls within the range recently reported by Yeh and colleagues. 71 If $1060, the lower end of Yeh’s range for lifetime PID costs, were used in our model, universal NAAT screening would remain the most cost-saving strategy.
Potential Effect of Refusals on Prevalence.
If all of those who refused participation were chlamydia-negative, then the overall prevalence would be reduced to 3.7%, yet universal screening would remain the most cost saving. On the other hand, if the chlamydia prevalence among those who refused were twice as high as those who participated, the overall prevalence would increase to 5.8%, but the proportion of missed cases would also increase from 9% to 35%. Nevertheless, universal screening would still save $36,000 and prevent 67 cases of PID as compared with no screening.
Our results suggest that universal chlamydia screening with a urine-based NAAT in a population of adolescent males entering detention is feasible and cost-effective. Many previous analyses have demonstrated the cost-effectiveness of chlamydia screening in a variety of asymptomatic female populations. 10–17 Young men, however, have not been as widely studied. 10,17–21 Although they suffer a small proportion of the sequelae associated with untreated infection, infected males continue to serve as a reservoir of infection for current and future female partners.
Now that sensitive and noninvasive testing is available, one major barrier to screening males has been removed. However, asymptomatic males rarely visit healthcare professionals. A recent Institute of Medicine Report has recommended providing comprehensive STD-related services within prisons and other detention facilities as one means of improving STD prevention. 24 Offering urine-based screening to this population of high-risk adolescent males provides an opportunity to detect and treat a substantial number of chlamydia infections. In fact, the majority of our infected study participants were asymptomatic and treated onsite at DYS; no infected participant was lost to follow up.
Despite the screening program success, 18% of eligible males declined participation. More than half of these males cited lack of interest as their reason for refusal. This limitation can be viewed as an indication that urine-based screening is not entirely acceptable; however, these young men declined to participate in a research study, and they could be more likely to agree to have their urine tested if testing was offered as part of the routine medical admission to DYS. In fact, previous studies have demonstrated a higher rate of acceptance of urine screening by detained adolescent males. 26,27 Because detainees are a vulnerable population, we emphasized their right to refuse research participation, which could have contributed to our relatively high refusal rate. Despite this, sensitivity analyses demonstrated that universal screening remained the most cost saving across a range of chlamydia prevalences for the population who refused screening.
Approximately half of the detainees were not offered testing during the prevalence study. However, urine collections occurred only once or twice weekly such that many youth could have been admitted and discharged between collection dates. Fortunately, the majority of detainees receive a cursory medical evaluation before discharge. Therefore, if chlamydia testing were incorporated into the routine admission protocol, then the proportion of detainees who are offered testing should approach 100%.
Our study differs from other chlamydia screening CEAs applied to male populations in important ways. Some did not include an LE screening strategy, 10,17,21 and a few were performed before the availability of NAATs. 18,20,21 The recent report by Ginocchio et al. is the most similar to our study; however, they came to very different conclusions. 19 Although they performed a CEA using the aggregated chlamydia prevalence from many different populations, including adolescents in juvenile detention, their estimates of treatment success and screening costs were not specific to a detention-screening venue. As a result, their analysis is more generalizable to diverse populations of males. Yet, we were specifically interested in the cost-effectiveness of screening adolescents entering detention. In contrast to our study, they concluded that selective NAAT screening of LE-positive asymptomatic males was the most cost-effective approach but was not cost saving.
The different conclusions between our study and Ginocchio et al.’s are likely the result of different parameter estimates for key variables, most notably the parameter estimate for NAAT cost. Whereas we derived an estimated NAAT cost of $10 from the literature, they estimated NAAT to cost $33 based on the maximum allowable Washington State Medicaid reimbursement. If a public health program relies on a commercial laboratory to process the NAAT, then the maximum allowable Medicaid reimbursement is a reasonable estimate to use. However, many public health laboratories could be performing their own NAAT processing, like the Massachusetts Department of Public Health is doing. In these situations, the cost incurred by the laboratory to process the specimens is more relevant than the maximum allowable Medicaid reimbursement. The LE sensitivity estimate is another key variable that impacts the CEA findings. Ginocchio et al.’s estimate for LE sensitivity (70%) was higher than what we demonstrated in our study (61.5%), and higher LE sensitivity favors the selective NAAT screening strategy.
As with any cost-effectiveness analysis, the results rely heavily on parameter estimates. Hence, it is imperative to carefully examine the effect of estimates made for those variables that the analysis is most sensitive to. Although males suffer from few if any sequelae of untreated chlamydia infections, the cost and morbidity resulting from sequelae among infected partners is substantial. 2 As a consequence, the majority of savings realized from universal chlamydia screening among this population of detained males is primarily the result of prevented PID and its sequelae in past and future female sexual partners. It is, therefore, not surprising that one of the categories of variables that our analysis was most sensitive to were estimates that factor in to the absolute cost of PID sequelae (eg, number of female partners, rates of PID development, and costs associated with chronic pelvic pain, ectopic pregnancy, and infertility).
Although we used primary data to determine an estimate for number of partners, our estimate is similar to ranges of 1.2 to 1.6 reported in the literature. 17,72 It is possible that we under estimated the number of female partners because for participants who reported greater than 2 past partners, we set the partner value equal to 3. However, these participants could have had more than 3 partners.
We assumed that treatment of chlamydia infection among detainees would prevent PID in both past and future partners. Most other analyses have not accounted for the multiplicative effect that frequent partner change has on the cost-effectiveness of screening males. However, concurrent partners and/or serial monogamy are not unusual among adolescent males. 72–74
The wide ranges of PID sequelae cost estimates found in the literature have a tremendous impact on the interpretation of the find-ings. We chose to use the midrange values but include the lowest values in a sensitivity analysis. Although the lowest values shifted the cost-effectiveness equation such that selective screening became more cost saving, universal screening remained most cost saving through most of the range. Furthermore, Yeh and colleagues recently reported on a comprehensive natural history model that they developed to provide a plausible range of average lifetime cost of PID. 71 Incorporating the lower end of their range into our analysis results in universal screening remaining the most cost-saving strategy.
This analysis was also sensitive to estimates of NAAT cost and LE performance. Although we used the highest NAAT cost estimate found in the literature, commercial charges are often substantially higher. Nevertheless, sensitivity analysis showed that NAAT cost would need to nearly double before universal screening was no longer favored. Most analyses of LE performance have used 1+ as the cutoff for a positive reading. We used trace+, which compromised specificity for improved sensitivity. However, previous studies of LE performance have not demonstrated both high sensitivity and specificity, and it is doubtful that LE performs as well as necessary to shift the favored strategy from universal screening to selective screening in our population of detainees.
Our results have limited generalizability because they are based on a specific population, namely, detained males. Nevertheless, 280,000 adolescent males are detained nationally each year. 75,76 Detection and treatment of chlamydia in this population could have a profound impact on the overall prevalence among young people who are members of the sexual networks in communities that detainees return to. Furthermore, It is possible for providers of detention health care in other regions to use our data to determine whether screening in their population is also cost-effective. If the chlamydia prevalence is at least 2.8% (threshold prevalence) and the majority of infected participants can be treated onsite (ie, test results received before participant’s discharge from facility), then it is likely that universal screening would be cost-effective.
In summary, we have demonstrated that universal chlamydia screening in a population of adolescent males entering detention was the most cost-effective strategy given that cost savings from prevented sequelae exceeded programmatic costs. Savings were primarily the result of the prevention of PID in recent and future female partners of index patients. Screening detained males using a urine-based NAAT provides a public health opportunity to substantially reduce chlamydia infections in youth at risk for STDs.
Modified Metaanalysis of Sensitivity and Specificity of Nucleic Acid Amplification Tests
To estimate the overall sensitivity and specificity of the 2 nucleic acid amplification assays used in this study, a Medline search was performed for all papers reporting on the performance of urine LCx or BDProbeTec for detecting chlamydia among males between 1966 and October 1, 2002. Search words used were Chlamydia trachomatis, ligase chain reaction, LCR, LCx, strand displacement amplification, SDA, Becton Dickinson, and BDProbeTec. Articles were included in the modified metaanalysis if chlamydia testing was performed on urine obtained from males and if at least 2 positive tests with discrepant analysis for discordant results were used as an enhanced gold standard.
Nineteen papers met criteria for inclusion in the analysis. 3–7,29–42 Data were pooled such that the total number of participants from all of the studies served as the denominator and the total number of infected participants from all of the studies served as the numerator for the pooled prevalence. Similarly, the total number of infected participants and the total number of detected infections served as the denominator and numerator, respectively, for the pooled sensitivity. Finally, the total number of uninfected participants and the total number of truly negative test results served as the denominator and numerator, respectively, for the pooled specificity.
Ten thousand four hundred fifty-four males (nLCx) participated in the LCx studies and 1094 of these men were infected with chlamydia (prevalence = 10.5%). The LCx detected 991 infections (sensitivity = 90.6%) and correctly identified 9302 true-negative results (specificity = 99.4%). Two thousand five hundred sixty-one males (nBD) participated in the BDProbeTec studies and 426 of these men were infected with chlamydia (prevalence = 16.6%). The BDProbeTec detected 401 infections (sensitivity = 94.1%) and correctly identified 2090 true-negative results (specificity = 98.0%).
Sensitivity and specificity were weighted according to the respective number of participants studied for each test:EQUATION
The weighted sensitivity and specificity for the combined LCx and BDProbeTec results were 91.3% and 99.1%, respectively. Cited Here...
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