Team:TUDelft/Human Practices/iHP

AptaVita AptaVita

Integrated Human Practices

The engagement with stakeholders, including experts, local healthcare workers, and health organizations, has shaped the design of our project. These interactions significantly influenced and helped to improve our design by calling our attention towards the real needs in Uganda regarding vitamin deficiencies.

Introduction

The goal of our Integrated Human Practices was to reflect on the human practices-related information obtained from stakeholders and experts and subsequently adapt our project design accordingly. We used a decision matrix for the adaptation that sets out the importance of the stakeholders' values per conflicting design options. Here, we report on the results of our integrated Human Practices. Firstly, we show the highlights through an interactive timeline briefly describing four different stages and what interaction with which stakeholder led to the underlying changes. Hereafter, we go more in-depth into (i) understanding the problem of micronutrient deficiency, (ii) defining and designing an impactful solution, and (iii) the final proposed implementation.

Interactive timeline

The interactive timeline includes all the design phases and the interviews that we conducted that led to these changes. For a phase description or the input and corresponding adjustments from the interviews, click on the figures in the interactive timeline.

Phase1 Martin_Van_Gijzen Mitasha_Bharadwaj RIVM Michel_Bengtson Joyce_Haddad Gain Ria_Reis Dr_Johnes_Obungoloch Roel_Kamerling Phase2 Phase3 Jan-Carel_Diehl Anonymous_health_org Dr_Moses_Ochora Healthy_Entrepreneurs Local_healthcare_surveying Phase4

Understanding the problem of micronutrient deficiency

To develop a new technology that contributes significantly to the battle against micronutrient deficiencies, we talked to various stakeholders to better understand the problem and to verify our assumptions about this problem. Literature showed us that micronutrient deficiencies are a worldwide problem, being most noticeably present in South-Asia and sub-Saharan Africa [7, 8]. However, it was found that the data is often incomplete or based on estimations. Therefore a clear need for improved data on micronutrient deficiencies was noticed [9]. Upon talking to Prof. Ria Reis, we decided on one country as a case study, Uganda, to limit our focus and thereby define our project to ensure the implementation to be as effective as possible. For further details on the contextualization of our project and the choice of Uganda as the target country, check our Human Practices page.

By interviewing Dr. Moses Ochora, we obtained information about current practices in Ugandan hospitals, which helped us understand the local context of micronutrient deficiencies in this country. He told us that many children suffer from micronutrient deficiencies, more specifically, iron, vitamin D, and folate. However, these children often come in when their symptoms are already irreversible. Currently, not many children get tested for micronutrient deficiencies, and therefore the exact numbers are unknown, complicating correct treatment. It became clear that for an effective solution to micronutrient deficiency, improved data is required. Moses told us that current vitamin testing methods are too expensive and that the samples have to be sent to external laboratories due to the minimal laboratory facilities at the hospitals. This is expensive and the laboratory tests can only be performed by skilled workers. This confirmed that limited data regarding micronutrient deficiency is due to expensive testing and limited infrastructure.

Dr. Johnes Obungoloch also confirmed that in Uganda, micronutrient deficiencies are a major problem. Due to the population's dependency on seasonal foods, the variety is limited, resulting in less diverse nutrient intake. However, he also mentioned that the general public is often unaware of the consequences of micronutrient deficiency and hence is not concerned with the problem. When citizens do think about the consequences, they often do not believe they have a choice to buy fresh foods because it is expensive.

The limited awareness about micronutrient deficiencies was mentioned in several conversations with experts, doctors, and health organizations. Therefore, time was also invested in learning about the necessary information about vitamins as can be seen from our collaborative Vitamin Cookbook. Moreover, we performed a survey amongst village healthcare worker teams (VHTs) who form the link between hospitals and the citizens in the villages. Furthermore, the VHTs already perform rapid diagnostic tests for tropical diseases, such as malaria, in rural areas. These VHTs are crucial in increasing awareness among citizens about the disastrous consequences of micronutrient deficiency. The VHTs feel that there is currently a lack of awareness regarding the health consequences of micronutrient deficiency. The unawareness of the village citizens will withhold them from getting tested for micronutrient deficiency. Other problems include the lack of funds and testing opportunities.

Health organizations gave us a better perspective on micronutrient deficiency worldwide. The Global Alliance for Improved Nutrition (GAIN) highly concerns itself with the battle against micronutrient deficiency. Oliver and Françoise from GAIN informed us about a recent biofortification project for folate in Ethiopia. They highlighted the importance of obtaining additional data on folate deficiency which we are targeting. The nutritional expert working at a global healthcare/monitoring organization informed us that the focus on vitamins also remains important in this organization and an integral part of their monitoring database. Furthermore, the World Health Organization (WHO) is continuously improving mapping vitamin deficiencies and sharing the data through their Vitamin and Mineral Nutrition Information System (VMNIS) database [10]. This showed us that health organizations would value quantitative data on micronutrient deficiencies and could use this to shape their intervention programs.

In short, these interviews helped us verify assumptions about the problem of micronutrient deficiency and understand the context in the target country. The vitamin testing capacity is low due to expensive tests and limited infrastructure. Furthermore, village healthcare workers are crucial in raising awareness about micronutrient deficiency, especially because the consequences of vitamin deficiency are unknown thereby complicating implementation. In the next section, "Defining and designing an impactful solution", you will read about the impact that stakeholder engagement had on the design of our solution for limited data availability on micronutrient deficiency.

Defining and designing an impactful solution

Besides a good understanding of the problem, a good understanding of the desired solution is essential to develop a novel, impactful, and responsible technology. As we desire to make AptaVita available for everyone, our case study focused on a low-income country, Uganda. Based on the value-sensitive design, an initial decision matrix was generated about design choices (Tab. 1). The decision matrix already shows some clashing values, such as safety and accuracy, and accessibility and quality. Due to these clashing values, compromises were made in the design choices. The input from stakeholders, such as experts, the local community, and health organizations, helped to prioritize certain values. Final design choices were decided upon through various semistructured interviews with stakeholders, as also shown in our interactive timeline.

Tab. 1 The initial decision matrix for design choices based on values from the value-sensitive design. The design choices include the type of sample, location of testing, type of cell-free system (CFS), production site, the substrate used in the CFS, the method for the test readout, and the screening target. These design choices were rated from negative to very positive based on the values of health, efficiency, quality, safety, trustworthiness, equality, sustainability, acceptability, and accessibility.
The initial decision matrix for design choices based on values from the Value-Sensitive Design

Obtaining the necessary samples

Initially, accessibility was high on the priority list, and therefore, the initial idea was to develop a self-test for vitamin testing. Self-testing would allow for easier screening of entire populations. Considering the value quality that was important to healthcare workers and health organizations, it was decided to use blood as a sample to detect vitamins. The concentrations of vitamins in the blood are considerably higher compared to vitamin concentrations in urine or saliva thereby contributing to a more accurate measurement [9]. However, the value of safety is at odds with the value of quality concerning blood samples. The National Institute for Public Health and the Environment and Prof. Ria Reis pointed out the dangers of spreading infectious blood diseases to which the vitamin detection test may be subjected. Therefore, the idea of self-testing had to be reconsidered. The test needs to be utilized in a safe environment with sterile needles and proper disposal. Hence, healthcare workers will perform the test in hospitals located in urban areas, as also recommended by Dr. Moses Ochora and Dr. Johnes Obungoloch.

Although the initial idea also consisted of testing in rural areas, Dr. Johnes Obungoloch told us that the healthcare facilities in these areas mainly consist of village healthcare workers. These village healthcare workers are often not trained to work with blood samples. Therefore, implementation of our vitamin detection test would be best suited for hospital environments, according to Johnes. Based on this information, the output of the VHT survey, and statistics of the Government of Uganda showing that 86% of the population has access to either a public or private hospital, we decided to focus on implementation in hospitals in urban and peri-urban areas [11]. However, to stimulate village citizens to get tested, intervention programs from the Ministry of Health are required. The citizens need to be taught about the consequences of micronutrient deficiency and they should be provided the necessary funds to get tested.


Morally responsible testing

As described in the previous section, initially, the idea was to develop a self-test for vitamin detection to allow people in rural areas with less access to healthcare to test for vitamin deficiency as well. Therefore, self-tests, resulting in individuals managing their health proactively, could improve early diagnosis and reduce health problems. However, upon talking to the experts, Dr. Jan-Carel Diehl and Dr. Johnes Obungoloch, we refrained from this idea. Self-test technology raises various ethical concerns. A risk for all diagnostic tests is the possibility of false-positive or false-negative results. However, the likelihood of obtaining a false positive or false negative result will increase when individuals conduct the test at home. This increase in the likelihood of obtaining false results might be due to individuals failing to conduct the test properly or due to misunderstanding the results of the test [12]. Another ethical concern of self-tests is that individuals at home are less likely to obtain sufficient support in either pre-diagnosis or post-diagnosis [12, 13]. Therefore, we decided that the test would need to be performed by healthcare workers. To minimize the possibilities for human error, the test will be analyzed by a dedicated hardware device, and a universal diagnosis will be given by a smiley readout as suggested by Prof. Ria Reis.

Another aspect that needs to be considered is that it is morally irresponsible to give a diagnosis without further treatment. Dr. Johnes Obungoloch told us that the lowest level of the healthcare system consists of village healthcare workers that only have limited qualifications. Moreover, these village healthcare workers often do not have the means to interfere if someone gets diagnosed with a certain disease. The only healthcare level that can ensure follow-up treatment includes private and public hospitals. Therefore, the decision was made to perform the tests in either public or private hospitals to ensure a follow-up treatment.


The detection system

Although the idea of PoC tests for low-resource settings is not new, no PoC tests for micronutrient deficiency testing are currently operational. To understand why no PoC tests are currently in use, we spoke to the nutritional expert working at a global health care/monitoring organization, who told us about common issues with PoC diagnostics. First of all, PoC tests need to compete with the accuracy of currently used methods. For AptaVita, this means that our test should be at least as accurate as high-performance liquid chromatography or mass spectrometry [14]. The value of quality was also highlighted by Dr. Moses Ochora, who worried about the multiplexing character of our test. The advantages of multiplex microfluidics testing are the easy sample loading by capillary forces and low price. However, the disadvantages include the low reproducibility of the test, high sample consumption, and the need for a control line for each parameter [15]. Therefore, it was decided to continue with a test without the multiplexing character. The multiplexing and microfluidics characters could be included in a later stage when the reproducibility of the test can be investigated and kept high.

Based on the importance of quality and accuracy, we decided on a cell-free system that is as robust and accurate as possible despite increased costs. Other common issues about PoC diagnostics raised by the nutritional expert working at a global health care/monitoring organization include the validation of tests in different communities on a small scale and a large scale, insufficient transport capacity, humidity, unavailable machinery in the local country, and permits. Based on these problems with current PoC testing, we tried to anticipate some of these problems. The REASSURED criteria that the PoC test should adhere to also states the importance of robustness. "Robustness refers to the ability of the test to withstand the supply chain (temperature, humidity, time delays, mechanical stresses) without requiring additional (and often costly) transport and storage conditions" [16]. Thus, the test should give the same output in dry and humid areas. Therefore, we tried to anticipate this issue by setting up a detailed protocol for an experiment to test the effect of humid conditions on our product AptaVita as can be found on our Results page.


Safety considerations of AptaVita

The iGEM competition and the Delft University of Technology iGEM team emphasize all aspects of safety in employing synthetic biology. Therefore, this year we have looked extensively into various safety aspects by means of a Safe-by-Design approach. This Safe-by-Design approach is shown in greater detail on our Safety page.

The first step in our safety evaluation was to determine the extent to which the product could adhere to upstream safety. Upstream safety refers to the safety of the product itself and its production process [17]. One of our main goals was to produce a product that adheres to inherent safety as much as possible. Therefore, we opted for a cell-free system as this includes all the machinery for transcription and translation that we require without working with an actual living organism. The usage of this cell-free system was also applauded by the National Institute for Public Health and the Environment. The Philosophical Table, see Education and Public Engagement for further details, showed that the "general" public did not directly see the advantages of using cell-free systems compared to genetically modified organisms. Therefore, research into the safety of cell-free systems and a clear explanation about their usage and potential advantages to the future users of the test is required.

Another design choice that was considered for inherent safety was the enzyme and thus also the corresponding substrate that we use for the colorimetric readout (Fig. 1). Initially, the gene XylE encoding the enzyme catechol-2,3-dioxygenase was incorporated in the plasmid to change from transparent to a yellow product upon conversion of the substrate pyrocatechol. Incorporating this XylE gene is relatively cheap and would therefore contribute to the affordability of the test. However, the substrate pyrocatechol has hazardous properties and had to be substituted considering the value of safety [18]. Therefore, it was decided to instead incorporate the gene LacZ encoding for the enzyme β-galactosidase requiring the substrate red-β-D-galactopyranoside.

The next step was to evaluate the downstream safety of the vitamin detection test. Downstream safety can apply to decision-making at other levels, such as biosecurity measurements determined by government policy [17]. To check for potential biosecurity issues, a dual-use quickscan was performed as a guideline. This analysis suggested that the main concern of our design was the misuse of data that would be collected from the vitamin testing. Dr. Jan-Carel Diehl also mentioned the downsides of a mobile phone readout for the vitamin test regarding privacy and security. The readout system was changed to dedicated hardware to eliminate some privacy issues, such as data storage on personal phones. Furthermore, to decrease the risk of data spreading, the vitamin test and the data collection procedure should adhere to the new Uganda National eHealth Strategy guidelines [19]. The final aspect considered for downstream safety includes the risks associated with a rapid diagnostic test that requires a blood sample. One of the major risks regarding blood tests is the risk of spreading infectious blood diseases. The decision was made to implement the test in hospitals due to the risks associated with infectious blood diseases. According to Dr. Johnes Obungoloch and Dr. Moses Ochora, hospitals are the safest to perform blood tests.


Readout for the test

Based on the REASSURED criteria and interviews with Dr. Martin van Gijzen and Dr. Michel Bengtson, we decided on a mobile phone readout instead of a visible readout. The REASSURED criteria address real-time connectivity which prioritizes standardization of data analysis [16]. Furthermore, a digital readout is convenient if the data should reach a database. Thus, a digital readout is necessary considering the goal to increase data availability of micronutrient deficiencies. Further in the process, we investigated the usage of dedicated hardware as recommended by Dr. Jan-Carel Diehl (Tab. 2).

Tab. 2 The advantages and disadvantages of a mobile phone readout and a dedicated hardware readout.
The advantages and disadvantages of a mobile phone readout and a dedicated hardware readout

Finally, it was decided to use a readout by a dedicated hardware device because of the possibility of controlling the temperature in which the test occurs and the higher accuracy due to constant light conditions (Tab. 2). The hardware will help to standardize the readout process, thereby decreasing the possibilities of human error. You can read more about the technical details of the designed hardware on our Hardware page.


Design of the dedicated hardware

The second conversation with Dr. Jan-Carel Diehl gave us new insights into the hardware and user interface design. Initially, the hardware was designed for loading one test at a time. However, the time for one test is approximately 45 minutes. Therefore, Jan-Carel recommended designing a hardware device with multiple slots to enable a larger capacity in busy hospitals. This can increase the capacity of the hardware and thereby also reduce the costs. These slots for multiple tests can be modular and changed according to capacity at the point of care.

The idea was to enable taking out the battery pack for charging. However, Jan-Carel pointed out that this also means that the battery pack can get lost more easily and that the battery pack might be valuable to people for other purposes. The design of the hardware must be adjusted in the future to have the battery pack secured in the hardware. The charging point for the battery pack can be a USB-C cable that will become universal and will simplify the charging process.

Finally, we need to make some changes to the user interface based on feedback from Jan-Carel. For pre-heating and uploading steps, a progress bar should be integrated to give healthcare workers a better indication about the remaining time. A universal smiley readout was already adopted with the words bad, fine, and good for the readout. However, the word "bad" sounds like bad news and does not necessarily encourage action. Therefore, we changed these words accompanying the smiley readout to "Take action" for a deficiency readout and "Well done" for positive micronutrient levels. In this way, behavior is directed more positively. For the uploading of the patient data, it was decided to incorporate a function to show a pop-up with "upload data" once the information for twenty patients has been gathered. This will reduce waiting time for a WIFI signal to upload the patient data. The data will be anonymously uploaded to protect privacy.

Implementation

To solidify our implementation vision of AptaVita into the health programs of governments, we looked at the overall overview of our project and ensured that all relevant values were incorporated into our project (Tab. 1). As explained earlier, we envisioned our test to be a self-test conducted by the entire population. However, with the input of Joyce Haddad, we adjusted our vision to targeting select communities as this would contribute to the achievement of our goals. Moreover, as pointed out by Dr. Johnes Obungoloch and Dr. Mitasha Bharadwaj, it turned out that the sampling and testing conducted by dedicated healthcare personnel are more viable. Therefore, we envision AptaVita to be conducted by healthcare workers in target communities. Check our Proposed Implementation page for a more detailed description.

To ensure the accessibility for our target group, the price of our product should be significantly below that of current detection methods. To analyze this, we conducted a market analysis and developed a business model. From this, it followed that the price of our test is 70% cheaper than the current tests available on the market and can therefore be sold to customers from low- and middle-income regions as it is more affordable. For more information, see our Entrepreneurship page.

Regarding the follow-up treatment after testing, it was decided to implement our product at hospitals to ensure the possibility of follow-up treatment. We have discussed both the option of vitamin pills and dietary advice as follow-up treatment with Dr. Moses Ochora and Dr. Johnes Obungoloch. Moses and Johnes were both advocates for dietary advice. Dietary advice could have long-term effects on health improvement, whereas vitamin pills would be a short-term solution. Moreover, these vitamin pills are often not affordable to the general population. Therefore, for our vitamin test to be a successful innovation, we require village healthcare workers to raise awareness about the importance of vitamins and give dietary advice. To make a start, we worked on a vitamin cookbook collaboration looking into traditional Ugandan dishes and how to improve their nutritional value, see also our Collaborations page.

References

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  11. Ministry of Health Uganda [@MinofHealthUG]. (2021, April 7). 86% of the population is now within a 5km reach of either a public or private health facility. [Tweet; image]. Twitter. https://twitter.com/MinofHealthUG/status/1379770295800696833
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