Intraobserver Reliability for S&F Teledermatology and Conventional Care
\r\n\tThe outcome of cancer therapy with radiation has been improving over the years due to technological progress. However, due to the biological property of cancer, current radiotherapy has limitations. Therefore, in consideration of the dynamics of tumor cells caused by radiation irradiation, attempts are being made to overcome the current drawbacks and to improve radiotherapy. It is expected that carbon ion beams, hyperthermia, oxygen effect, blood flow control, etc. will be used in the future in order to improve the treatments. This book aims to introduce research results of various radioprotective agent development research and hypoxia sensitizers.
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It offers many benefits that include increased access to dermatologic services and potential reduction in costs associated with care. Teledermatology is traditionally categorized into two different models based on the technology that is employed: store-and-forward (S&F) teledermatology, and live, interactive (LI) teledermatology (Goldyne & Armstrong, 2010). While hybrid models (a combination of S&F and LI technology) are practiced at selected institutions, this chapter focuses primarily on S&F and LI models. We will present operational flows of these two technology-enabled modalities, common outcomes measures used for evaluation of teledermatology quality metrics, and economic analyses.
\n\t\t\tAt the end of the chapter (in section 5), we will consider a novel, technology-independent framework for categorizing teledermatology models as well. This system relies on classification of teledermatology based on healthcare delivery models, and serves as an alternative way to organize and evaluate the provision of teledermatologic care.
\n\t\tStore-and-forward teledermatology is an asynchronous means for providing dermatologic care, as it relies on the
In the S&F model, a medical staff personnel at the referral site typically takes images of the relevant skin condition and obtains medical history. This information is then sent to a dermatologist via a secure internet connection. The dermatologist evaluates the patient’s condition asynchronously and transmits the recommendations back to the primary care provider at the referral site (Pak et al., 2009).
\n\t\t\tTeledermatology studies have assessed numerous outcomes measures, including learning effects, length of consultation, and technical aspects (Eminovic et al., 2007). We will focus this discussion on four extensively used outcomes measures: diagnostic accuracy, diagnostic reliability, clinical outcomes, and satisfaction.
\n\t\t\t\tDiagnostic accuracy refers to whether or not a diagnosis is correct, based on comparison to a gold standard reference test. While histopathological review or other laboratory tests are often used as the gold standard for diagnosis, results of these types of gold standards are not always available in clinical practice in dermatology. Furthermore, it is difficult to generate cumulative data regarding accuracy, because different studies use different methodologies and standards.
\n\t\t\t\t\tSeveral studies have found diagnostic accuracy of S&F teledermatology to be comparable to in-person consultations (Barnard & Goldyne 2000; High et al., 2000; Krupinski et al., 1999; Oakley et al., 1997; Whited et al., 1999). Other studies have found that in-person consultation provides a significantly greater diagnostic accuracy than S&F teledermatology (Warshaw et al. 2009a; Warshaw et al. 2009b). One study found that S&F teledermatology had a significantly greater diagnostic accuracy than in-person consultation (Lozzi et al., 2007).
\n\t\t\t\t\tDifferent findings on diagnostic accuracy may be attributable to several factors. First, the “gold standard” used among the studies differ from in-person evaluations to pathologic evaluation. Second, patient populations and types of skin lesions differ among the various practices that were examined. Future studies can focus on tools or interventions to increase diagnostic accuracy of S&F teledermatology, such as routine incorporation of dermoscopy (Warshaw et al., 2010a).
\n\t\t\t\tDiagnostic reliability is a measure of concurrence in diagnosis. It may refer to intraobserver reliability (whether one examiner makes the same diagnosis in two different examinations), or interobserver reliability (whether two different examiners make the same diagnosis). These measures of reliability may evaluate either complete agreement, which refers to comparison of the most likely diagnosis, or partial agreement, which accounts for differential diagnoses.
\n\t\t\t\t\tStudies of intraobserver reliability between S&F teledermatology and in-person consultation found that agreement ranges between 31-88% for complete diagnostic agreement, and between 50-95% for partial diagnostic agreement (Table 1).
\n\t\t\t\t\tReference | \n\t\t\t\t\t\t\t\tComplete Diagnostic Agreement | \n\t\t\t\t\t\t\t\tPartial Diagnostic Agreement | \n\t\t\t\t\t\t\t
(Romero et al., 2010) | \n\t\t\t\t\t\t\t\t.85 | \n\t\t\t\t\t\t\t\t.92 | \n\t\t\t\t\t\t\t
(Tan et al., 2010) | \n\t\t\t\t\t\t\t\t.74 | \n\t\t\t\t\t\t\t\t.88 | \n\t\t\t\t\t\t\t
(Heffner et al., 2009) | \n\t\t\t\t\t\t\t\t.82 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Ebner et al., 2008) | \n\t\t\t\t\t\t\t\t.74 | \n\t\t\t\t\t\t\t\t.90 | \n\t\t\t\t\t\t\t
(Pak et al., 2003) | \n\t\t\t\t\t\t\t\t.70 | \n\t\t\t\t\t\t\t\t.91 | \n\t\t\t\t\t\t\t
(Lim et al., 2001) | \n\t\t\t\t\t\t\t\t.88 | \n\t\t\t\t\t\t\t\t.95 | \n\t\t\t\t\t\t\t
(Taylor et al., 2001) | \n\t\t\t\t\t\t\t\t.31-.64 | \n\t\t\t\t\t\t\t\t.50-.70 | \n\t\t\t\t\t\t\t
(Krupinski et al., 1999) | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t\t.76-.90 | \n\t\t\t\t\t\t\t
Intraobserver Reliability for S&F Teledermatology and Conventional Care
Studies have found that interobserver reliability ranges between 41-92% for complete diagnostic agreement and between 51-100% for partial diagnostic agreement (Table 2). A review of studies between 1997 and 2005 revealed that the aggregate complete diagnostic agreement was 60%, and partial diagnostic agreement was 80% (Romero et al., 2008).
\n\t\t\t\t\tReference | \n\t\t\t\t\t\t\t\tComplete Diagnostic Agreement | \n\t\t\t\t\t\t\t\tPartial Diagnostic Agreement | \n\t\t\t\t\t\t\t
(Tan et al., 2010) | \n\t\t\t\t\t\t\t\t.75-.82 | \n\t\t\t\t\t\t\t\t.83-.89 | \n\t\t\t\t\t\t\t
(Heffner et al., 2009) | \n\t\t\t\t\t\t\t\t.69 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Silva et al., 2009) | \n\t\t\t\t\t\t\t\t.87-.92 | \n\t\t\t\t\t\t\t\t.96-1.0 | \n\t\t\t\t\t\t\t
(Edison et al., 2008) | \n\t\t\t\t\t\t\t\t.73 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Ebner et al., 2008) | \n\t\t\t\t\t\t\t\t.71-.76 | \n\t\t\t\t\t\t\t\t.90-.97 | \n\t\t\t\t\t\t\t
(Bowns et al., 2006) | \n\t\t\t\t\t\t\t\t.55 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Oakley et al., 2006) | \n\t\t\t\t\t\t\t\t.53 | \n\t\t\t\t\t\t\t\t.64 | \n\t\t\t\t\t\t\t
(Tucker & Lewis, 2005) | \n\t\t\t\t\t\t\t\t.56 | \n\t\t\t\t\t\t\t\t.68 | \n\t\t\t\t\t\t\t
(Baba et al., 2005) | \n\t\t\t\t\t\t\t\t.75 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Mahendran et al., 2005) | \n\t\t\t\t\t\t\t\t.44-.48 | \n\t\t\t\t\t\t\t\t.64-.65 | \n\t\t\t\t\t\t\t
(Du Moulin et al., 2003) | \n\t\t\t\t\t\t\t\t.54 | \n\t\t\t\t\t\t\t\t.63 | \n\t\t\t\t\t\t\t
(Eminovic et al., 2003) | \n\t\t\t\t\t\t\t\t.41 | \n\t\t\t\t\t\t\t\t.51 | \n\t\t\t\t\t\t\t
(Lim et al., 2001) | \n\t\t\t\t\t\t\t\t.73-.85 | \n\t\t\t\t\t\t\t\t.83-.89 | \n\t\t\t\t\t\t\t
(Taylor et al., 2001) | \n\t\t\t\t\t\t\t\t.44-.51 | \n\t\t\t\t\t\t\t\t.57-.61 | \n\t\t\t\t\t\t\t
(High et al., 2000) | \n\t\t\t\t\t\t\t\t.64-.77 | \n\t\t\t\t\t\t\t\t.81-.89 | \n\t\t\t\t\t\t\t
(Whited et al., 1999) | \n\t\t\t\t\t\t\t\t.41-.55 | \n\t\t\t\t\t\t\t\t.79-.95 | \n\t\t\t\t\t\t\t
(Lyon & Harrison, 1997) | \n\t\t\t\t\t\t\t\t.89 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Zelickson & Homan, 1997) | \n\t\t\t\t\t\t\t\t.88 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Kvedar et al., 1997) | \n\t\t\t\t\t\t\t\t.61-.64 | \n\t\t\t\t\t\t\t\t.67-.70 | \n\t\t\t\t\t\t\t
Interobserver Reliability for S&F Teledermatology and Conventional Care
Based on this data on diagnostic reliability, it appears that S&F teledermatology is a functional and reasonably reliable tool for diagnosis of skin disorders.
\n\t\t\t\tTo date, two studies have evaluated clinical outcomes of S&F teledermatology compared to conventional care, and both studies found similar outcomes for each of the two treatment modalities (Krupinski et al., 2004; Pak et al., 2007). Specifically, Pak et al. conducted a randomized controlled trial with patients randomly assigned to either conventional face-to-face care or teledermatology. Another dermatologist, blinded to the randomization, evaluated the clinical outcomes between baseline data and after four months (Table 3). The results suggest that teledermatology and conventional care result in similar outcomes (Pak et al., 2007).
\n\t\t\t\t\t\n\t\t\t\t\t\t\t\t | Clinical Course Rating | \n\t\t\t\t\t\t\t|||
Improved | \n\t\t\t\t\t\t\t\tNo change | \n\t\t\t\t\t\t\t\tWorse | \n\t\t\t\t\t\t\t||
Assigned Group | \n\t\t\t\t\t\t\t\tTeledermatology | \n\t\t\t\t\t\t\t\t64% | \n\t\t\t\t\t\t\t\t33% | \n\t\t\t\t\t\t\t\t4% | \n\t\t\t\t\t\t\t
Conventional Care | \n\t\t\t\t\t\t\t\t65% | \n\t\t\t\t\t\t\t\t32% | \n\t\t\t\t\t\t\t\t3% | \n\t\t\t\t\t\t\t
Reported Clinical Outcomes from Pak et al
We may also consider intermediate clinical outcomes, such as (1) time-to-intervention and (2) preventable clinic visits. Time-to-intervention is usually defined as the wait time prior to being seen by a specialist after a referral has been placed. Preventable clinic visits refers to the percentage of dermatology clinic visits that could be avoided through use of teledermatology.
\n\t\t\t\t\tThe literature suggests that the use of S&F teledermatology may considerably reduce time-to-intervention. Researchers in Spain found that surgical patients managed through S&F teledermatology had a mean waiting interval 34.47 days shorter than those patients managed through conventional care (Ferrandiz et al., 2007). A similar study found that patients at primary care centers managed through teledermatology waited on average 76.31 days less than those with conventional referrals (Moreno-Ramirez et al., 2007). A study of patients at the Durham VA Medical Center found that those that received a S&F teledermatology consultation were seen on average 86 days sooner than those in the conventional system (Whited et al., 2002).
\n\t\t\t\t\tThe reduced time-to-intervention may be partially due to the fact that teledermatology can help prevent unnecessary clinic visits. Indeed, studies have found that S&F teledermatology could prevent 13-58% of dermatology clinic visits (Whited, 2010).
\n\t\t\t\tSatisfaction assessments may be subdivided into three categories: patient satisfaction, referring provider satisfaction, and specialist satisfaction. Studies suggest that patients were generally satisfied with receiving care through S&F teledermatology, and typically had no preference between teledermatology and usual care (Warshaw et al., 2010b). One study found that 76% of patients preferred being treated through teledermatology in order to avoid the wait time associated with a face-to-face clinic visit (Bowns et al., 2006). A common patient complaint during the S&F teledermatology process was the length of time between the consultation and being informed of the results by the primary care providers (Whited, 2010).
\n\t\t\t\t\tWhen referring providers were asked about their satisfaction with S&F teledermatology, referring providers provided varied feedback (Bowns et al., 2006; Collins et al., 2004; Weinstock et al., 2002; Whited et al., 2004). Many referring providers report that they improved their therapeutic and diagnostic ability due to regular feedback and interactions with the dermatologist (van den Akker et al., 2001). From the referring providers’ perspective, some dissatisfaction with the S&F teledermatology process stemmed from the additional time and effort required for relaying the diagnoses to patients, prescribing the medications, or performing procedures (Bowns et al., 2006; Collins et al., 2004; Kvedar et al., 1999).
\n\t\t\t\t\tFewer studies have evaluated satisfaction of dermatologists who practice teledermatology. While most dermatologists practicing teledermatology reported increased satisfaction (Whited, 2010), many report reduced confidence in their diagnoses (Bowns et al., 2006; Pak et al., 1999; Whited et al., 2004).
\n\t\t\t\tWe begin discussion of the economic aspects of S&F teledermatology with a brief review of common types of economic analysis. Three commonly used methods are cost minimization analysis, cost-effectiveness analysis, and cost-benefit analysis (Davalos et al., 2009). Cost-minimization analysis is a type of cost analysis that evaluates two systems that produce equivalent outcomes. Cost-effectiveness analysis compares monetary costs (cost) in the context of outcomes (effectiveness). However, this type of analysis generally considers only one outcomes measure. In comparison, cost-benefit analysis considers multiple economic costs as well as varied benefits within a system, and it generally includes multiple outcomes measures. Cost-benefit analyses are generally considered the most comprehensive type of economic analyses. Further information regarding economic evaluation metrics may be found in Davalos et al. (Davalos et al., 2009).
\n\t\t\t\tLiterature shows that S&F teledermatology is generally economically viable (Table 3). While studies differed in their economic perspective and modality of S&F teledermatology delivery (e.g. triage, consultation, versus provision of care), analyses have generally established that S&F teledermatology offers a cost-effective means of providing dermatologic care especially for those living in geographically isolated communities or medically underserved communities (Pak et al., 2009; Whited et al., 2003). For example, in a cost-minimization analysis that adopted the perspective of the U.S. Department of Defense, Pak et al. concluded that the use of teleconsultations through S&F technology reduced overall costs compared to conventional care (Pak et al., 2009).
\n\t\t\t\tSimilarly, Whited et al. performed a cost analysis of a consultative model using S&F technology from the perspective of the U.S. Department of Veterans Affairs (Whited et al., 2003). The authors found that teleconsultations are $15 more costly per patient compared to face-to-face consultation. In this study, effectiveness was defined as time-to-specialist evaluation. They found that having teledermatology consultations resulted in shorter time-to-specialist evaluation and was overall more cost-effective. Further analyses showed that, from a
When S&F teledermatology was used as a primary method for triaging cases appropriate face-to-face encounters, researchers found that this was an economically viable means for prioritizing patients requiring dermatologic care (Ferrandiz et al., 2008; Moreno-Ramirez et al., 2009). By comparing S&F teledermatology and conventional referrals to a skin cancer clinic in Spain, Moreno-Ramirez et al. conducted a cost-identification and cost-effectiveness analysis from a societal perspective (Moreno-Ramirez et al., 2009). The investigators assessed costs associated with travel, lost-productivity, and healthcare delivery. Effectiveness was defined as the wait-time to in-person consultation after the referral. The authors found that teledermatology triage was more cost-effective; specifically, teledermatology yielded cost-savings of €49.59 per patient compared with conventional face-to-face care (Moreno-Ramirez et al., 2009). These findings were corroborated by another cost-effectiveness study in Spain, where the investigators found that the use of teledermatology saved €122.02 compared to conventional care (Ferrandiz et al., 2008).
\n\t\t\t\tReference | \n\t\t\t\t\t\t\tType of Analysis | \n\t\t\t\t\t\t\tTeleconsultation | \n\t\t\t\t\t\t\tConventional | \n\t\t\t\t\t\t\tPerspective | \n\t\t\t\t\t\t
Provision of Care | \n\t\t\t\t\t\t||||
(Pak et al., 2009) | \n\t\t\t\t\t\t\tCost-minimization | \n\t\t\t\t\t\t\t$340 / patient | \n\t\t\t\t\t\t\t$372 / patient | \n\t\t\t\t\t\t\tDepartment of Defense | \n\t\t\t\t\t\t
(Whited et al., 2003) | \n\t\t\t\t\t\t\tCost / Cost-effectiveness | \n\t\t\t\t\t\t\t$36.40 / patient | \n\t\t\t\t\t\t\t$21.40 / patient | \n\t\t\t\t\t\t\tDepartment of Veterans Affairs | \n\t\t\t\t\t\t
Triage | \n\t\t\t\t\t\t||||
(Moreno-Ramirez et al., 2009) | \n\t\t\t\t\t\t\tCost-identification / Cost-effectiveness | \n\t\t\t\t\t\t\t€79.78 / patient | \n\t\t\t\t\t\t\t€129.37 / patient | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
(Ferrandiz et al., 2008) | \n\t\t\t\t\t\t\tCost / Cost-effectiveness | \n\t\t\t\t\t\t\t€156.40 / patient | \n\t\t\t\t\t\t\t€278.42 / patient | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
$ - US dollars; € - euros | \n\t\t\t\t\t\t
Economic Analyses of Store-and-Forward Teledermatology
Live, interactive teledermatology involves synchronous interaction between the specialist and patient (Goldyne & Armstrong, 2010). Via videoconferencing or web-conferencing, the specialist obtains a clinical history, examines the patient in real-time, and communicates recommendations to the patient and the primary care provider (Wootton et al., 2000).
\n\t\t\tWe will consider the same outcomes measures for LI teledermatology as we did for S&F teledermatology: diagnostic accuracy, diagnostic reliability, clinical outcomes, and satisfaction.
\n\t\t\t\tStudies comparing diagnostic accuracy of LI teledermatology to pathologic diagnosis are not currently available. Studies comparing diagnoses between LI teledermatology and in-person consultation generally show diagnostic agreement, and will be discussed further under diagnostic reliability.
\n\t\t\t\tStudies of intraobserver reliability between LI teledermatology and in-person consultation show complete diagnostic agreement in 59-75% of cases, and partial agreement in 76-87% of cases (Table 5).
\n\t\t\t\t\tReference | \n\t\t\t\t\t\t\t\tComplete Diagnostic Agreement | \n\t\t\t\t\t\t\t\tPartial Diagnostic Agreement | \n\t\t\t\t\t\t\t
(Loane et al., 1998b) | \n\t\t\t\t\t\t\t\t.71 | \n\t\t\t\t\t\t\t\t.87 | \n\t\t\t\t\t\t\t
(Gilmour et al., 1998) | \n\t\t\t\t\t\t\t\t.59 | \n\t\t\t\t\t\t\t\t.76 | \n\t\t\t\t\t\t\t
(Oakley et al., 1997) | \n\t\t\t\t\t\t\t\t.75 | \n\t\t\t\t\t\t\t\t.82 | \n\t\t\t\t\t\t\t
Intraobserver Reliability for LI Teledermatology
Interobserver reliability between LI teledermatology and in-person consultation ranges from 54-80% for complete diagnostic agreement, and 79-99% for partial agreement (Table 6). A review of aggregate data indicates that complete diagnostic agreement is 70%, while partial diagnostic agreement is 84% (Romero et al., 2008).
\n\t\t\t\t\tReference | \n\t\t\t\t\t\t\t\tComplete Diagnostic Agreement | \n\t\t\t\t\t\t\t\tPartial Diagnostic Agreement | \n\t\t\t\t\t\t\t
(Nordal et al., 2001) | \n\t\t\t\t\t\t\t\t.72 | \n\t\t\t\t\t\t\t\t.86 | \n\t\t\t\t\t\t\t
(Phillips et al., 1998) | \n\t\t\t\t\t\t\t\t.59 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Loane et al., 1998b) | \n\t\t\t\t\t\t\t\t.60 | \n\t\t\t\t\t\t\t\t.76 | \n\t\t\t\t\t\t\t
(Lowitt et al., 1998) | \n\t\t\t\t\t\t\t\t.80 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
(Gilmour et al., 1998) | \n\t\t\t\t\t\t\t\t.54 | \n\t\t\t\t\t\t\t\t.80 | \n\t\t\t\t\t\t\t
(Lesher et al., 1998) | \n\t\t\t\t\t\t\t\t.78 | \n\t\t\t\t\t\t\t\t.99 | \n\t\t\t\t\t\t\t
(Phillips et al., 1997) | \n\t\t\t\t\t\t\t\t.77 | \n\t\t\t\t\t\t\t\t- | \n\t\t\t\t\t\t\t
Interobserver Reliability for LI Teledermatology
One study evaluated clinical outcomes for LI teledermatology compared to conventional care. In a retrospective analysis of patients who had two or more teledermatology consultations, Marcin et al. found that diagnosis, treatment, and patient improvement data for the teledermatology patients were consistent with existing literature regarding conventional care (Marcin et al., 2005).
\n\t\t\t\t\tIntermediate outcomes measures include (1) preventable clinic visits and (2) time for completion of consultation. Similar to the S&F modality, LI teledermatology can prevent unnecessary clinic visits. Studies found that 44.4-82% of clinic visits could be avoided through the use of LI teledermatology (Whited, 2010).
\n\t\t\t\t\tLI teledermatology can decrease total time necessary to complete a consultation visit from the patient’s perspective. For example, researchers in New Zealand found that, compared to a clinic visit, the use of LI teledermatology saved patients an average of 3.45 hours of time, primarily due to reduced traveling time (Oakley et al., 2000). However, LI teledermatology does not necessarily reduce consult time for the dermatologist (Loane et al., 1999, 2001b; Oakley et al., 2000).
\n\t\t\t\tAs stated previously, satisfaction in teledermatology is categorized into patient satisfaction, referring provider satisfaction, and dermatologist satisfaction. Patients reported that they were equally satisfied with LI teledermatology and conventional care and had no strong preference for one modality over another (Whited, 2010). Some patients reported initial discomfort due to the presence of camera (Gilmour et al., 1998; Loane et al., 1998a).
\n\t\t\t\t\tRelatively few studies evaluated referring provider satisfaction in LI teledermatology. While there was some dissatisfaction associated with technical difficulties, most referring providers report being satisfied with the LI teledermatology (Gilmour et al., 1998; Jones et al., 1996).
\n\t\t\t\t\tSimilar to dermatologists who practice S&F teledermatology, dermatologists who practice LI teledermatology report being satisfied with practicing LI teledermatology. However, when compared to in-person consultation, dermatologists expressed lower confidence in their diagnoses (Artiles Sanchez et al., 2004; Lowitt et al., 1998).
\n\t\t\t\tEconomic analyses of LI teledermatology yielded mixed conclusions regarding its economic sustainability. While some studies have shown LI teledermatology to be cost-effective, others suggested that it may be more costly than conventional care. In a cost-minimization analysis from a societal perspective, authors from New Zealand found that teledermatology consultations using LI technology appeared less costly than that of face-to-face care, especially when patients have longer travel distances (Loane et al., 2001b). In another cost-minimization study of LI teledermatology in the U.S., investigators found that consultative teledermatology using LI technology also appears to be less costly than face-to-face care from a provider perspective (Armstrong et al., 2007).
\n\t\t\t\tIn a cost-benefit analysis from the societal perspective, Wootton et al. found that a LI teleconsultation system in the United Kingdom was more costly than face-to-face care. Sensitivity analyses showed that LI teledermatology consultations could be a less costly alternative if patients travelled longer distances for in-person consultations and incurred greater lost-productivity costs (Wootton et al., 2000).
\n\t\t\t\tReference | \n\t\t\t\t\t\t\tType of Analysis | \n\t\t\t\t\t\t\tTeleconsultation | \n\t\t\t\t\t\t\tConventional | \n\t\t\t\t\t\t\tPerspective | \n\t\t\t\t\t\t
(Dekio et al., 2010) | \n\t\t\t\t\t\t\tCost-effectiveness | \n\t\t\t\t\t\t\t¥26,040 / week | \n\t\t\t\t\t\t\t¥60,500 / week | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
(Armstrong et al., 2007) | \n\t\t\t\t\t\t\tCost-minimization | \n\t\t\t\t\t\t\t$274 / hour | \n\t\t\t\t\t\t\t$346 / hour | \n\t\t\t\t\t\t\tHealthcare provider | \n\t\t\t\t\t\t
(Loane et al., 2001b) | \n\t\t\t\t\t\t\tCost-minimization | \n\t\t\t\t\t\t\tNZ$279.23 / patient | \n\t\t\t\t\t\t\tNZ$283.79 / patient | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
(Loane et al., 2001a) | \n\t\t\t\t\t\t\tCost-benefit | \n\t\t\t\t\t\t\t£146.48 / patient | \n\t\t\t\t\t\t\t£47.13 / patient | \n\t\t\t\t\t\t\tUrban Societal | \n\t\t\t\t\t\t
(Loane et al., 2001a) | \n\t\t\t\t\t\t\tCost-benefit | \n\t\t\t\t\t\t\t£180.22 / patient | \n\t\t\t\t\t\t\t£48.77 / patient | \n\t\t\t\t\t\t\tRural Societal | \n\t\t\t\t\t\t
(Wootton et al., 2000) | \n\t\t\t\t\t\t\tCost-benefit | \n\t\t\t\t\t\t\t£132.10 / patient | \n\t\t\t\t\t\t\t£48.73 / patient | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
(Lamminen et al., 2000) | \n\t\t\t\t\t\t\tCost | \n\t\t\t\t\t\t\tFM 18,627 (total cost) | \n\t\t\t\t\t\t\tFM 18,034 (total cost) | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
(Bergmo, 2000) | \n\t\t\t\t\t\t\tCost-minimization | \n\t\t\t\t\t\t\tNKr 470,780 (total cost) | \n\t\t\t\t\t\t\tNKr 1,635,075 (total cost) | \n\t\t\t\t\t\t\tHealthcare provider | \n\t\t\t\t\t\t
(Chan et al., 2000) | \n\t\t\t\t\t\t\tCost / Cost-effectiveness | \n\t\t\t\t\t\t\tHK$57.7 / patient | \n\t\t\t\t\t\t\tHK$322.8 / patient | \n\t\t\t\t\t\t\tHealthcare provider | \n\t\t\t\t\t\t
(Burgiss et al., 1997) | \n\t\t\t\t\t\t\tCost | \n\t\t\t\t\t\t\t$141 / patient | \n\t\t\t\t\t\t\t$294 / patient | \n\t\t\t\t\t\t\tSocietal | \n\t\t\t\t\t\t
¥ - yen; € - euros; $ - US dollars; NZ$ - New Zealand dollars; £ - pounds; FM – Finnish marks; NKr – Norwegian kroners; HK$ - Hong Kong dollars | \n\t\t\t\t\t\t
Economic Analyses of Live, Interactive Teledermatology
Approximately 42% of the United States population lives in medically underserved areas (Suneja et al., 2001). Both S&F and LI teledermatology can increase access to specialty care especially for populations living in rural or medically underserved areas (Hailey, 2005; Kailasam et al., 2010; Pak et al., 2007; Vallejos et al., 2009).
\n\t\t\tS&F and LI teledermatology present distinct advantages. S&F teledermatology appears to be very cost-effective. Specifically, compared to LI teledermatology, S&F teledermatology requires less equipment or technology costs (Pak, 2008; Watson, 2009). The requirements for administrative support and overhead also appear to be less for S&F teledermatology. Finally, the asynchronous nature of S&F modality affords greater scheduling flexibility for patients and dermatologists since coordinated appointments with specialists are not required (Finch et al., 2007; Watson, 2009). LI teledermatology, on the other hand, more closely mirrors a conventional face-to-face consultation because the specialist can interact with patients and a referring provider in real-time.
\n\t\t\tS&F and LI teledermatology have their respective disadvantages as well. In S&F teledermatology, because the ability of the dermatologist to diagnose and provide useful recommendations depends solely on the quality of images and clinical history, suboptimal images or incomplete clinical history can be frustrating for the dermatologist. Furthermore, S&F teledermatology does not allow the development of a patient-dermatologist relationship compared to LI teledermatology (Grenier et al., 2009; Onor & Misan, 2005). LI teledermatology presents alternative challenges in terms of scheduling, coordination, and costs.
\n\t\t\tGiven the unique benefits that each modality offers, some providers have recently started to employ a hybrid model. In the hybrid model, the clinical encounters are conducted via videoconferencing or webconferencing, and the dermatologist reviews static digital images that were acquired by a digital camera prior to the encounter and sent to them during the encounter. Current research efforts are investigating the relative effectiveness of such hybrid systems (Baba et al., 2005; Romero et al., 2010). For example, Baba et al. found that a hybrid modality increased diagnostic accuracy by 7-9%, compared to S&F teledermatology alone (Baba et al., 2005).
\n\t\tTo date, teledermatology has been categorized by the technology it uses--S&F and LI technology. An alternative model to frame teledermatology is based on the type of healthcare delivery. Specifically, independent of the type of technology employed, we can arrange teledermatology delivery into (1) triage, (2) consultative, and (3) direct-care models. This technology-independent, healthcare delivery-based framework is accessible to policy makers and other stakeholders involved in health policy.
\n\t\t\tIn the triage model, all dermatology referrals are first seen through teledermatology. A specialist reviews the cases rapidly with the goal of prioritizing which patients are suitable for in-person evaluation. The triage model prioritizes patients based on the severity and urgency of their skin condition. This modality has been primarily practiced in Europe in prioritization patients with cutaneous malignancies (Ferrandiz et al., 2007; Moreno-Ramirez et al., 2007).
\n\t\t\tIn the consultative model, the referring providers decide which dermatology referrals are appropriate for teledermatology evaluation. From the dermatologist’s perspective, the primary goal of the consultative model is to provide detailed and useful recommendations to the primary care provider. In this healthcare delivery model, the dermatologist reviews the cases via either S&F or LI technology and provides detailed recommendations to the primary care provider. The primary care provider assumes responsibility for communicating with the patient and carrying out the recommendation plans. The consultative model is currently the most common model in the United States (Goldyne & Armstrong, 2010).
\n\t\t\tIn the direct-care model, the dermatologist assumes the responsibility of communicating and treating the patient. This model differs significantly from the triage or consultative model in that the dermatologist is responsible for caring for the patient. The provision of direct care includes evaluation, communicating the treatment plan to the patient, writing prescriptions, carrying out laboratory evaluations, and monitoring disease progression.
\n\t\t\t\tThe direct-care model has generally been practiced using S&F technology and in research settings (Chambers et al., 2010; Parsi et al., 2010; Watson et al., 2010).
\n\t\t\tAs healthcare delivery becomes more patient-centered and distance-independent (Hibbard, 2004; Hogarth et al., 2010; Robinson et al., 2011), proper application of teledermatology offers a versatile means of providing high quality care to patients in their own communities. Teledermatology can be used in various healthcare delivery modalities, including triage, consultation, and direct care.
\n\t\t\tIn addition to gathering the support of healthcare workers and patients for these newer models of healthcare delivery, those who work at the forefront of telemedicine need to also advocate for policy changes and technological innovations to continually improve the quality and experience of telemedicine. It is likely that the cost of technology will decline as the reliability and user-interface of technology continually improve. In this healthcare environment, innovations in teledermatology serve as examples for emerging paradigms in healthcare delivery.
\n\t\tResearch was initiated in the early 1990s which led in 2000 to the publication of the technology behind what came to be known as Golden Rice [1, 2]. From the outset, the intention was to create a source of vitamin A in the endosperm of rice, as an additional intervention for vitamin A deficiency. Philanthropy and the public sector funded the research [1]. In 2001, the inventors, Professor Ingo Potrykus and Dr. (now Professor) Peter Beyer, assigned their patents to Syngenta for commercial exploitation as part of a transaction which obliged the company to assist the inventors’ humanitarian and altruistic objectives [1, 3, 4]. At the same time, the nutritional technology was donated by its inventors for use in developing countries [3, 4]. The inventors licenced a network of Asian government-owned rice research institutes to deliver their objectives. Product development was initiated through the International Rice Research Institute (IRRI) and the network. The whole network, including IRRI, worked to a common set of goals defined in licences each institution signed with the inventors. The terms included that there would be no charge for the nutritional technology and it would only be introduced to publicly owned rice varieties. Improvements were made to the technology by Syngenta scientists [5]. In 2005 and 2006, pursuant to Syngenta’s legal obligations entered into with the inventors in 2001, Syngenta provided selected transformation events of the improvements to the Golden Rice Humanitarian Board. The Humanitarian Board, via Syngenta and IRRI, made these new versions available to the Golden Rice licensee network [4, 6]. In 2004 Syngenta ceased its commercial interest in Golden Rice [7]. From 2004 development was again only funded by philanthropy and the public sector; the national budgets of Bangladesh, China, India, Indonesia, Philippines and Vietnam; as well as the US National Institutes of Health together with the Rockefeller and Bill & Melinda Gates Foundations and USAID. Golden Rice is a not-for-profit project: no individual, nor organisation involved with its development, has any financial interest in the outcome.
To date the Golden Rice project has principally engaged plant scientists. Activist opposition to Golden Rice has been led principally by non-scientists, who have been very successful in developing a narrative about Golden Rice and gmo crops which serves the activist’s purpose1 but is fundamentally inaccurate [8]. Further background to the development of Golden Rice, including the political dimensions, is detailed elsewhere [6, 9, 10].
A few years ago, at Tufts University, USA, I gave a presentation about Golden Rice. The symposium was organised by the Friedman School of Nutrition Science and Policy whose strategic aims today include ‘Reduce nutrition-related health inequities’ and ‘Promote food systems that increase agricultural sustainability while improving human health’ [11]. I was dismayed to learn that the anti-gmo and anti-Golden Rice activists’ narrative was widely accepted by the participants—all of whom were studying or working in nutrition and well aware of nutritional inequities in public health.
Without adoption, that is, regular growth and consumption of Golden Rice by populations in countries where rice is the staple and VAD is problematic, Golden Rice cannot deliver any public health and welfare benefits. Adoption requires cooperative working by different specialists, including medical, nutritional and public health specialists [12]. This chapter is designed to answer anticipated questions from such specialists, to facilitate adoption of Golden Rice as an additional intervention for vitamin A deficiency.
Rice is the most important staple crop [6]: more than half of the global population eats it every day. In some countries, 70–80% of an individual’s calorie intake is from consumption of rice [13, 14].
For storage without becoming rancid, the husk and the aleurone layer of rice have to be removed. What remains after polishing-white rice, the endosperm-contains small amounts of fat and is an excellent source of carbohydrate for energy but contains no micronutrients. Yet humans require both macronutrients (carbohydrates, proteins, fats) and micronutrients (minerals and vitamins) for a healthy life. Like all plants, rice obtains its minerals from the soil. Vitamins are synthesised by plants and/or animals, including humans.
Human health is best served by a ‘balanced diet’ that is varied, containing both macronutrients and micronutrients, including animal products and, as sources of provitamin A, coloured fruits and vegetables. Micronutrient sources are insufficiently represented in the diets of many people in countries where rice is the staple. The reasons often include poverty: such dietary components are expensive compared to the cost of rice [15]. In countries where rice is the staple, the average consumption is 75.20 kg/capita/year. Of those countries where micronutrient deficiencies are common, consumption increases to 150 kg/capita/year [16]. In such populations micronutrient deficiencies, like poverty itself, often occur as part of an intergenerational cycle [17].
For the past 15 years, 800 million people—more than 10% of the global population—are hungry every day. These chronically hungry individuals lack sufficient calories in their daily diet [18, 19, 20]; indeed over the past 3 years, the trend is upward [20]. Even more alarming is that 2 billion people—almost 25% of global population—are micronutrient deficient; they suffer from ‘hidden hunger’, with important associated morbidity and mortality [17] and related economic impact [6, 17]. Figure 1 shows that over the 20-year period 1990–2010, the rate of reduction of chronic hunger (that is, macronutrient—carbohydrate, proteins and fats—dietary insufficiency) has been faster than the rate of reduction for hidden hunger (that is, dietary insufficiency of minerals and vitamins) [21] Dr. Matin Qaim, member of the Golden Rice Humanitarian Board and one of the authors of the paper from which Figure 1 is extracted, has commented: ‘In the future the hidden hunger [e.g. micronutrient deficiency] burden will be larger, [than chronic hunger – principally carbohydrate deficiency] unless targeted efforts to reduce micronutrient malnutrition are implemented at larger scale’ (pers comm: Dr. M Qaim).
Disability-adjusted life years (DALYs) lost due to chronic hunger and hidden hunger between 1990 and 2010. Please refer to text for further explanation (
Interventions for micronutrient deficiencies include
With the creation of Golden Rice in 1999 [2]—the first purposefully created biofortified crop—a new term was required: ‘biofortification’. The word was first used in 2002 [23] and first defined in 2004 [24]: “biofortification” is a word coined to refer to increasing the bioavailable micronutrient content of food crops through genetic selection via plant breeding.’ In 2003 ‘Harvest Plus’ a not-for-profit public-sector programme started to biofortify staple crops by conventional plant breeding, to benefit the poor, and progress with biofortification through conventional plant breeding was rewarded by the World Food Prize in 2016 [25].
The intention of biofortification is to deliver public health benefits to populations which are micronutrient deficient, through consumption of the staple crop including the extra nutrition within the edible part of the crop. In this way minimal cultural change is required to food—production, processing or consumption—systems. For the most marginal members of the population, this biofortification approach overcomes the inherent access, cost and non-sustainability difficulties of supplementation and fortification. In 2017 the World Bank recommended that biofortified staple crops should be the norm rather than the exception: ‘conventionally’ bred biofortified crops and also genetically engineered crops—gmo crops—were both recommended with Golden Rice specifically mentioned [26].
For Golden Rice to deliver benefits, it has to be grown and consumed within target countries where VAD remains problematic despite significant progress with other interventions, notably vitamin A capsules, which have undoubtedly saved millions of lives and will save more, since they were introduced (accompanied by controversy) in the 1990s [15, 22]. And success or failure with Golden Rice will directly affect future adoption also of high zinc, high iron and high folate rice and their impact on public health for hundreds of millions of people. All these traits, introduced to the endosperm of rice, necessitated using gmo techniques [16, 27], and all cost no more than white rice to the grower or consumer. Eventually, as the end point of product development, it is planned to include all these nutritional traits together in multi-micronutrient-Golden Rice.
Adoption of Golden Rice requires public health professionals as well as agricultural and other professionals, to work together in each country [12]. Any scepticism created by the past 18 years of negative activist influence will prevent success, if not positively addressed by all involved. For billions of people, the stakes could not be higher.
For more than a quarter of a century, vitamin A deficiency (VAD) has been recognised by the United Nations as a significant public health problem. Key milestones included the:
VAD control is the most cost-effective child health/survival strategy governments can pursue.
All sectors of society should support the virtual elimination of VAD.
Strategies should include promoting breast-feeding, dietary diversification, vitamin A supplementation and food fortification.
Locally available food-based strategies are the first priority. Vitamin A capsule supplementation is only an interim measure [29].
Nevertheless, vitamin A deficiency (VAD) remains a major public health problem, in more than half of all countries, especially in Africa and south-east Asia (Figure 2), hitting hardest young children and pregnant women [31] especially in countries where rice is the staple food. Food sources that are most valuable in terms of micronutrients—for vitamin A, animal products including milk, eggs, butter, liver and fish—are usually more expensive and ‘beyond the reach of poor families’ [15]. Food security staple crops such as rice are cheaper and therefore make up most of the diet.
Public health importance for vitamin A deficiency, by country. Source [
The problem of VAD is exacerbated by the limited bioavailability of vitamin A from fruit and vegetables [33]. It has been estimated that young children between ages 1 and 3 years would need to eat eight servings of dark green leafy vegetables per day in order to meet the recommended dietary allowance (‘RDA’) for vitamin A. These facts have resulted in the conclusion of ‘the virtual impossibility for most poor, young children to meet their vitamin A requirements through vegetable and fruit intake alone’ [15].
VAD is the principal cause of irreversible blindness in children [34]. Another morbidity of VAD is related to impairment of the immune system [15]: most children and mothers who die as a result of VAD do not become blind first but die of common childhood diseases. VAD is a
Global mortality (millions) | 2010a | 2014a | 2016/2017 |
---|---|---|---|
Vitamin A deficiency | 1.9–2.8 | 1.4–2.1 | 1.3–1.9 (2016)b |
HIV/AIDS | 1.8 | 1.2 | 0.94 (2017)c |
Tuberculosis (TB) | 1.4 | 1.1 | 1.6 (2017)d |
Malaria | 0.7 | 0.6 | 0.45 (2016)e |
Annual mortality from different public health diseases (VAD deaths exclude significant maternal mortality).
Source: [6]
Source: 23–34%—see text—of 5.6 months <5 years children in 2016 [37]
Source: http://www.unaids.org/en/resources/fact-sheet [Accessed: January 10, 2019]
Source: https://www.who.int/news-room/fact-sheets/detail/tuberculosis [Accessed: January 10, 2019]
Source: https://reliefweb.int/report/world/world-malaria-report-2017 [Accessed: January 10, 2019]
In 2016, 26 years after the first UN commitment to
There is not one type of Golden Rice. The ‘genetic modification’ part of the process used to create Golden Rice occurred only once, in about 2004 [5]. The preferred ‘transformation event GR2E’ was selected in late 2013 [6, 9] and subsequently introduced by ‘conventional plant breeding’ into more than a dozen cultivars of the
The agronomy of Golden Rice—how it grows, its resistance to pests and diseases, its water requirements and days to maturity and plant and grain morphologies—and yield are the same as the variety into which the nutritional trait has been introduced. An avoidable human error was made in an earlier selection of ‘a lead transformation event: GR2R’, which led to plants in open fields falling over when subject to wind and rain, and a small yield loss of about 2% was the result [9, 38]. GR2R was dropped from development in late 2013. The current lead transformation event, GR2E, was selected in the same year. GR2E has been, and will be, registered for use and has no problems associated with it [6].
In his wonderful book
Nevertheless, for Golden Rice ‘from a public health standpoint, for food fortification to be effective’, all the characteristics listed by Dr. Semba are satisfied, except when it comes to ‘undetectable by persons consuming it’. The Golden Rice colour is caused by the β-carotene content, a source of vitamin A for humans, which in Golden Rice is about 80–90% of all carotenoids [5]. It is the same β-carotene which colours mangos, papaya, squash and carrots, all of which consumers readily accept, and there is no taste associated with the β-carotene content. In Golden Rice, the intensity of the colour is proportional to the β-carotene content. The colour is obvious and cannot be ignored (Figure 3).
Polished white and Golden Rice and (a different cultivar, after 2 months of postharvest storage) after cooking.
In 2009 MBA students at the Asian Institute of Management conducted qualitative attitudinal surveys of small farmers and consumers in four different representative island locations in the Philippines. Neither the colour nor the way it was created was considered a block to trying Golden Rice, so long as it was expected to assist their family’s health and was affordable. The solid colour of Golden Rice was recognisably distinct from the rather blotchy yellow colour of poorly stored white rice, which is sometimes offered cheaply by governments to assist poor people.
From several perspectives the colour of Golden Rice is positive. Consumers have a choice about whether to select it for cooking and whether to consume it or not. Such consumer choice is denied and therefore only made by governments or plant breeders, when the biofortified trait is ‘undetectable by persons consuming it’ [15], as in the case of invisible biofortificants such as iron or zinc introduced into biofortified grain crops or used in fortification of processed food. The colour of Golden Rice makes the consumers’ choice clear, even in populations with a variety of languages and dialects or where individuals are illiterate: each grain of Golden Rice is individually labelled, by its colour. No labelling is required on any packaging, and preference can be beneficially affected by communication of its lack of any adverse associations, and anticipated health benefits, from consumption.
Eighty percent—about 380 million tonnes—of global rice production is produced on small farms for family consumption, usually unprocessed except for polishing [38]. It is probably not stored for long, as rice is produced, usually, in two or three growth cycles annually, and storage facilities are limited. Data have shown that degradation of the β-carotene is minimal 2 months after harvest and samples of Golden Rice stored in ambient temperatures for 4.5 years remain noticeably yellow, indicating continued presence of β-carotene [39].
In early 2001, a year after the seminal paper describing the ‘proof of concept’ technology [2], Greenpeace made a press release: ‘Genetically modified “Golden Rice” containing provitamin A will not solve the problem of malnutrition in developing countries,… Greenpeace calculations show… , that an adult would have to eat at least 3.7 kilos of dry weight rice, i.e. around 9 kilos of cooked rice, to satisfy their daily need of vitamin A from “Golden Rice” …’ [40].
It is unclear how Greenpeace came to their conclusion. At the time, it was known that the bioavailability of carotenoids is influenced by nine different factors [41]. But no one knew how efficiently the β-carotene in Golden Rice was converted to circulating vitamin A, retinol, by human adults or children. And nutritionists agreed that animal models would not be helpful because animals metabolise carotenoids differently than humans. Research was needed to determine how efficiently the β-carotene in Golden Rice is converted to circulating retinol, in children in developing countries where rice is the staple, the population segment which suffers most from VAD.
A February 2002 grant application to the US governments National Institutes of Health (NIH) for a project, which is entitled ‘Retinol Equivalents of Plant Carotenoids in Chinese Children’, states ‘This project is to determine the vitamin A value (equivalence) of dietary provitamin A carotenes from spinach, Golden Rice, and pure β-carotene (β-c) in oil. These experiments will be conducted in children (ages 6–8) with/without adequate vitamin A nutrition’.
On February 10, 2004, Tufts University Institutional Review Board (IRB) approved the research Protocol for ‘Retinol Equivalents of Plant carotenoids in Chinese Children’ and noted that ‘The Zhejiang Academy of Medical Sciences [China] approval is on file’.
On March 11, 2008, the Tufts IRB reviewed and on May 10, 2008, approved the study ‘Vitamin A Value of Plant Carotenoids (Spinach and Golden Rice in Children)’ based on the Protocol ‘Retinol equivalents of plant carotenoids in Chinese children’. Both Protocols referenced ‘NIH grant proposal 1R01 DK060021’.
On March 30, 2008, with respect to ‘Retinol Equivalents of Plant carotenoids in Chinese Children’ and ‘NIH Grant 1R01 DK060021-01’: The Ethical Review Committee of Zhejiang Academy of Medical Sciences confirmed that they had ‘reviewed the proposed use of human subject identified on June 27, 2003’ and certified that ‘the approval notice is still valid’.
Although the Chinese children research was planned in 2003, various practical setbacks in the production2 of the deuterium-labelled Golden Rice [9] meant that the field work in China was not completed until mid-June 2008 and, due to the complexity of analysis combined with limited analytical resources, publication not until 2012.
In the meantime, similar research was approved and conducted with adult volunteers in the USA. Data confirmed that 3.8 molecules of β-carotene derived by consumption of a single meal of Golden Rice converted to one molecule of circulating retinol [42]; this 3.8:1 bioconversion compared very favourably with conversion ratios established using other plant sources [33]. When the Chinese children research were published online on August 8, 2012, the authors reported a bioconversion ratio of 2.3:1.0, later adjusted to 2.1:1.0, and neither ratio significantly different, statistically, from the 2.0:1.0 of β-carotene in oil, another treatment in the same research. A third treatment, spinach, showed a 7.5:1.0 conversion. In each case the sophisticated research design measured the efficiency of conversion of β-carotene to circulating retinol following a single meal containing the β-carotene source. The publication noted that ‘In summary, the high bioconversion efficiency of Golden Rice β-carotene to vitamin A shows that this rice can be used as a source of vitamin A. Golden Rice may be as useful as a source of preformed vitamin A from vitamin A capsules, eggs or milk to overcome VAD in rice-consuming populations’ [4, 6].
These results were clearly very different from Greenpeace’s 2001 prediction. Instead of welcoming the excellent news of a potentially useful additional VAD intervention, Greenpeace, on August 29, 2012, issued a further press release in China from their Netherlands HQ: ‘Greenpeace alarmed at US-backed GE food trial on Chinese children’…‘It is incredibly disturbing to think that an American research body used Chinese children as guinea pigs for genetically engineered food,… The relevance of this study is questionable,…Nor does high conversion rate solve all the technical, environmental and ethical issues around Golden Rice’ [6, 10]. Greenpeace claimed that the Chinese authorities agreed to halt the research before it started3 but were unable to substantiate their claim to an independent journalist. The press release created hysteria in China and, 4 years after the field research had been completed, caused the parents of the subject children consternation.
Tufts University IRB carried out an investigation and concluded that there were ‘no concerns related to the integrity of the study data, the accuracy of the research results or the safety of the research subjects. In fact, the study indicated that a single serving of the test product, Golden Rice, could provide greater than 50 percent of the recommended daily intake of vitamin A in these children, which could significantly improve health outcomes if adopted as a dietary regimen’. Tufts also noted that ‘the research itself was found not to have been conducted in full compliance with IRB policy or federal regulations’ [43].
Eventually following this Greenpeace Press release, Tang et al. (2012) was retracted by the American Society of Clinical Nutrition in 2015 for procedural reasons. The full details of this and other impediments to Golden Rice’s development are given elsewhere [6, 9, 10, 43].
Separately, the Chair of the Tufts IRB, a computer scientist, in complaint to the publisher of one critical review of the case [10], wrote: ‘There was no research ethics committee or IRB review and approval in effect for the study when it was conducted in 2008’. This gross error of fact, with reference to the NIH grant and related IRB authorisations quoted above, itself calls into question the professionalism or objectivity of the 2012 Tufts IRB review which led to the retraction. (The research sophistication and quality of the retracted paper can be reviewed online [44]).
Henry Miller, a physician, molecular biologist and the founding director of the US Food and Drug Administration (FDA), commented in 2015 on the retracted paper: ‘A 2012 article in the nutrition literature might have been the most momentous contribution to public health worldwide since Dr. Jonas Salk’s announcement of the polio vaccine. The operative phrase is might have been, because intimidation, politics and the dishonest, anti-science efforts of NGOs to impugn the research have delayed the translation of its findings to life-saving interventions for millions of children. Why do anti-genetic engineering activists want to save the whales but let children go blind and die?’ [45].
The data generated by the above-mentioned research allow determination of the proportion of the estimated average requirement (EAR) the β-carotene content of Golden Rice can provide to children and adults (Table 2). If Golden Rice was the sole source of β-carotene in the diet, 50% of the EAR is sufficient to combat VAD [46]. Many nutritionists consider that supply of 30–40% of the EAR will be sufficient to combat VAD because the biofortified staple crop is seldom the only source of β-carotene. (The recommended daily allowance—RDA—which implies maintenance of 3-months liver stores of vitamin A, is not required to combat VAD.) The calculations (Table 2) use the β-carotene levels observed in different Golden Rice cultivars (e.g. RC82, BR29, IR36, IR64) of Golden Rice GR2E 2 months after harvest, when degradation has stabilised. A 6% loss of β-carotene in cooking Golden Rice, or 25% loss of β-carotene when a Golden Rice meal is parboiled first, and then reheated, has not been taken into account.
Amount of β-carotene in Golden Rice μg/g | Rice consumption per day (g of dry rice before cooking) | Percentage of EAR provided | |
---|---|---|---|
4.0 | 40 | 36% | |
4.0 | 100 | 91% | |
6.0 | 40 | 54% | |
6.0 | 100 | 136% | |
11.2 | 40 | 102% | |
11.2 | 100 | 254% | |
4.0 | 40 | 20% | |
4.0 | 100 | 50% | |
6.0 | 40 | 30% | |
6.0 | 100 | 75% | |
11.2 | 40 | 56% | |
11.2 | 100 | 140% |
The potential for Golden Rice to deliver the estimate average requirement of β-carotene, as a source of vitamin A, to 1–3-year-old children and adults.
For 1- to 3-year-old child, 100% of EAR is 210 μg RAE/day. An EAR that does not ensure adequate stores but is enough for normal dark adaptation is set at 112 μg ~50% EAR [46]
Golden Rice differs from white rice only in that it contains β-carotene, that is, provitamin A, which the human body converts to vitamin A. Golden Rice contains no vitamin A itself. So the question about safety relates principally to β-carotene, which is anyway ubiquitous in a balanced human diet and the environment.
At the levels found in food, β-carotene is a safe source of vitamin A, and classed as ‘generally recognised as safe’ (GRAS), by the United States Food and Drug Administration (US FDA) [47, 48]. At these physiological doses, consumption of β-carotene over several years has no adverse health effects [49, 50, 51, 52]. The human body only converts to vitamin A, in the form of circulating retinol, the amount of β-carotene necessary, with the rest being excreted or stored unchanged in body tissues (e.g. fat, liver, etc.). It is impossible to induce vitamin A toxicity by consuming β-carotene (pers. comm. Dr. R Russell).
In all β-carotene-containing crops, immediately after harvest the level of β-carotene reduces. For Golden Rice carotenoid degradation mechanisms have been thoroughly investigated4 and the products of degradation quantitated. Additionally, 102 plant food items from Philippine markets, together with orange- or yellow-coloured soft drinks, as well as non-gmo field grown, in all cases, orange maize cobs and yellow cassava storage roots from Zambia, and orange-fleshed sweet potato tubers from Uganda, were analysed for the cleavage products of β-carotene, apocarotenoids [53]. The potential risks arising from ‘aberrant plant carotenoid synthesis’ [54] in genetically modified plants, including Golden Rice, or from non-gmo crops biofortified with pro-vitamin A, have been thoroughly investigated, the authors reporting that ‘Our analysis and quantification of β-carotene derived cleavage products across biofortified and non-biofortified crop plant tissues combined with the calculation of potential exposure document no reason for concern’ [53].
For the formal regulatory approvals for the use of a gmo crop in food, as animal feed or in food or feed processing, on a country by country basis, detailed data sets have to be submitted. For permission to grow a gmo crop in a country, additional data have to be generated5 and submitted showing environmental safety.6 The ‘food, feed and processing’ data package developed for Golden Rice GR2E is extensive (42 megabytes of data). It is available without cost to all Golden Rice licensee countries consistent with long-standing Golden Rice Humanitarian Board policy. Here are the key summaries of the regulatory data submission made in the Philippines:
Although it is hard to imagine that such golden grains of polished Golden Rice could be included in commercial shipments of white rice by accident, in the modern world, any such inclusion could be damaging to international trade. To prevent even such an unlikely situation, the Golden Rice regulatory data have been submitted to regulatory authorities in countries which import rice, where VAD is not a public health issue. As a result of these data submissions, Golden Rice GR2E has been confirmed as safe for use as food, in feed, and for processing by the government’s regulatory authorities in Australia, Canada, New Zealand and USA. The regulatory deliberations and decisions are publicly available: Australia and New Zealand,8 Canada9 and the USA.10
Because in these industrialised countries rice forms only a tiny proportion of standard diets which already contain ample sources of vitamin A, the amounts of β-carotene in Golden Rice would have no significant additional nutritional benefit there. Comments to this effect by the US regulatory authorities were implied by anti-gmo crop opponents to be applicable also in developing countries where the dietary situation is completely different. Such implication has been rebutted by the US FDA [55]. The regulators in these industrialised countries concurred with Tufts University’s statement issued after their investigation of the ‘Chinese children’ research: ‘… Golden Rice, …could significantly improve health outcomes if adopted as a dietary regimen’ [43].
Further regulatory submissions have been made, and registrations are expected, in countries where VAD is a public health problem [56]. In the Philippines the process is not yet complete; nevertheless various government departments have already expressed their support.11
Gmo crops have been vilified by activist groups since the 1990s. ‘Frankenstein foods’ were used in a letter in the
Notwithstanding this opposition, all independent scientific institutions globally have determined, for many years, that there is no inherent danger to crop plants, or the human use of crops plants, or the environment from transferring genes from one organism to another, to create gmo crops, also known as genetically engineered (GE) crops, including transfer of genes between species which cannot sexually reproduce to transfer the genes ‘naturally’ [6, 58, 59].
Norero [60] provides a list of more than 240 independent science institutions from all over the globe which have commented on the safety of the techniques of genetic modification. A particularly clear reference comes from the heart of the geography politically most opposed to gmo technology, the European Commission of the European Union:
‘The main conclusion to be drawn from the efforts of more than 130 research projects, covering a period of more than 25 years of research and involving more than 500 independent research groups, is that biotechnology, and in particular GMOs, are not per se more risky than, for example, conventional plant breeding technologies’ [61].
At the time of writing, 141 Nobel Laureates, of about 290 living, have signed an open letter dated June 29, 2016, addressed to the leaders of Greenpeace, the United Nations and governments around the world calling for the campaign against Golden Rice specifically, and crops and foods improved through biotechnology in general, to cease ‘Opposition based on emotion and dogma contradicted by data must be stopped’ [8]. The letter also has the support of more than 13,000 other scientists and citizens.
Golden Rice seed and regulatory data packages are available—without cost—to public-sector rice-breeding institutions in less developed countries where rice is the staple and vitamin A deficiency endemic. Supply is subject only to national and international regulations and simple and free agreements [4]. The licences ensure that the inventor’s, Professors Potrykus and Beyer, objectives for their donated technology cannot be frustrated: only publicly owned rice varieties can be used, and the nutritional trait cannot be ‘stacked’ with any other gmo trait, unless the latter is also under the control of the public sector. There will be no charge to growers or consumers for the nutritional trait: Golden Rice will cost the same as white rice. Golden Rice homozygous seed, which breeds true generation to generation, will be provided by public-sector rice breeders. All small-holder family farmers—responsible for 80% of global rice production [38]—will eventually have access to it, with (except for commercial export—not a resource-poor farmer activity) no limitations on planting or replanting, harvest or sale of seed or grain.
Addressing micronutrient malnutrition, including VAD, is consistently ranked by the Copenhagen Consensus process, as the first, or at least within the top 5, most cost-effective investments with the potential to address the world’s 30 most intractable problems [62, 63, 64]. Investing in alleviating malnutrition would repay $45 for each dollar invested compared with $36 from fighting malaria and $10 from combatting HIV [65].
Compared with the World Bank standard, or the full cost of provision of vitamin A capsules, a common dietary supplement intervention for VAD since the early 1990s [15, 22], the cost of Golden Rice to save each disability-adjusted life year (DALY) is expected to be very low, perhaps US$0.5 [9, 66, 67].
Economists have calculated that conservative adoption of Golden Rice would benefit the gross domestic product (GDP) of Asian countries by US$6.4 billion (value in US$ of 2005) annually through increased productivity enabled by reduced vitamin A deficiency-induced sickness, and improved eyesight, and ~US$17.4 billion (value in US$ of 2005) if Golden Rice adoption encouraged adoption of other nutritional traits in rice [68]. Recently, HarvestPlus has exceeded target levels of iron and zinc in rice, which they were unable to achieve by conventional breeding, using gmo techniques [16]. Genetic modification has also been used to introduce folate into rice endosperm [27, 69]. The delay to the introduction of Golden Rice in India has been calculated to have cost Indian GDP US$199 million per annum for the decade from 2002 [70, 71], in total about US$1.7 billion (value in US$ of 2014).
Adoption of biofortified crops, including Golden Rice, will facilitate attainment of six of the most important Sustainable Development Goals 2015–2030 (Table 4). The standard costs used by the economists referenced in Tables 3 and 4 [62, 63, 64, 66, 67] refer to the costs of supplementation with vitamin A capsules. As when using Golden Rice, the vitamin A source has zero cost to the grower or consumer; the cost benefit of Golden Rice will be very significantly better than using vitamin A capsules.
Costs (US$ of 2006) | Highest efficiency | Lowest efficiency | ||
---|---|---|---|---|
World Bank cost-effective standarda | $200 | $200 | ||
Providing vitamin A capsulesa | $134 | $599 | ||
Vitamin A fortification of fooda | $84 | $98 | ||
Golden Rice, India @ 12:1a | $3.10 | $19.4 | ||
Golden Rice, Bangladesh 6:1b & 12:1c | $4.0b | $54.0c | ||
Golden Rice, abovea,b,c adjusted 2.1:1d | $0.5 | $1.4 | $3.4 | $9.5 |
Relative costs of saving one disability-adjusted life year using different sources of vitamin A and, for Golden Rice, different bioconversion ratios of β-carotene to circulating vitamin A.
The earlier studies occurred before these bioconversion ratios had been elucidated
Goal # | Goal | Potential impact of biofortification |
---|---|---|
1 | No poverty | Micronutrients in staple crops reduce effects |
2 | Zero hunger | Whole populations will be micronutrient sufficient |
3 | Good health | Provitamin A, Fe, Zn, Folate: less morbidity and mortality |
4 | Quality education | Pupils learn when adequately fed: Fe important |
5 | Gender equality | Biofortified staples available to whole population |
7 | Decent work and economic growth | Increased productivity from biofortified rice alone will add US$17.4 (in US$ of 2005) to Asian GDP |
Biofortification and some Sustainable Development Goals 2015–2030.
Vitamin A deficiency remains a huge public health problem despite existing interventions. Biofortification of staple foods is a new policy priority internationally. Golden Rice is safe. There is excellent human evidence that it will work. It is expected to be extremely cost-effective.
For successful adoption of Golden Rice as an additional intervention for vitamin A deficiency, the support of public health professionals is critical.
Dr. Robert Russell chaired the ‘panel on micronutrients’ the output of which, published in 2001 [72], created the US Governments’ dietary reference intakes for 14 micronutrients, including vitamin A. Also, in 2001, he joined the Golden Rice Humanitarian Board. I am grateful for his nutritional advice and instruction over the intervening years and for checking my calculations in connection with Table 2 and the surrounding text. I have known Dr. Guangwen Tang almost as long and thank her for providing, years ago, copies of the original documents which allowed me to construct with confidence the chronology of the IRB permissions 2003 and 2008 in the USA and China, all referring to the same NIH grant. Since 2015, the project has benefited from another specialist professional, Dr. Donald MacKenzie, who, aside from managing the GR2E regulatory data package generation, compilation and submissions, has also provided the web-links, which I have listed as footnotes in the ‘Safety’ section of this chapter. Thank you, Don, for your critically important work.
The author declares no conflict of interest.
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\n\n*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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